Substituted piperidines as CCR3 antagonists

ABSTRACT

Object of the present invention are novel substituted compounds of the formula 1, 
                         
wherein A, R 1 , R 2 , R 3  and R 4  are defined as in the description. Another object of the present invention is to provide antagonists of CCR3, more particularly to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

Object of the present invention are novel substituted compounds of theformula 1,

wherein R¹, R², R³ and R⁴ are defined as in the description. Anotherobject of the present invention is to provide antagonists of CCR3, moreparticularly to provide pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt thereof.

BACKGROUND INFORMATION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J. Med., 338,436-445 (1998); Rollins, Blood, 90, 909-928 (1997); Lloyd, Curr OpinPharmacol., 3, 443-448 (2003); Murray, Current Drug Targets., 7, 579-588(2006); Smit, Eur J. Pharmacol., 533, 277-88 (2006)

There are two major classes of chemokines, CXC and CC, depending onwhether the first two cysteines in the amino acid sequence are separatedby a single amino acid (CXC) or are adjacent (CC). The CXC chemokines,such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-Ia, MIP-1, the monocyte chemotactic proteins (MCP-1,MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, mast cells, dendritic cells, and basophils. Also inexistence are the chemokines lymphotactin-1, lymphotactin-2 (both Cchemokines), and fractalkine (a CXXXC chemokine) that do not fall intoeither of the major chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seventransmembrane-domain proteins (reviewedin Horuk, Trends Pharm. Sci., 15, 159-165 (1994); Murphy, PharmacolRev., 54 (2):227-229 (2002); Allen, Annu. Rev. Immunol., 25, 787-820(2007)) which are termed “chemokine receptors.” On binding their cognateligands, chemokine receptors transduce an intracellular signal throughthe associated trimeric G proteins, resulting in, among other responses,a rapid increase in intracellular calcium concentration, activation ofG-proteins, changes in cell shape, increased expression of cellularadhesion molecules, degranulation, promotion of cell migration, survivaland proliferation. There are at least eleven human chemokine receptorsthat bind or respond to CC chemokines with the following characteristicpatterns: CCR-1 (or “CKR-1” or “CC—CKR-1”) [MIP-Ia, MCP-3, MCP-4,RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng.J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B”or “CC—CKR-2A”/“CC CKR-2B”) [MCP-1, MCP2, MCP-3, MCP-4, MCP-5] (Charo etal., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng.J. Med., 338, 436-445 (1998)); CCR3 (or “CKR-3” or “CC—CKR-3”)[eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J.Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338,436-445 (1998)); CCR-4 (or “CKR-4” or “CC—CKR-4”) [TARC, MIP-Ia, RANTES,MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or “CKR-5” OR “CCCKR-5”)[MIP-Ia, RANTES, MIP-Ip] (Sanson, et al., Biochemistry, 35, 3362-3367(1996)); CCR-6 (or “CKR-6” or “CC—CKR-6”) [LARC] (Baba et al., J. Biol.Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or “CC—CKR-7”) [ELC](Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8”or “CC—CKR-8”) [1-309, TARC, MIP-1p] (Napolitano et al., J. Immunol.,157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588(1998)); CCR-10 (or “CKR-10” or “CC—CKR-10”) [MCP-1, MCP-3] (Bonini etal, DNA and Cell Biol., 16, 1249-1256 (1997)); and CCR31 (or “CKR-11” or“CC—CKR-11”) [MCP-1, MCP-2, MCP-4] (Schweickart et al., J Biol Chem, 2759550-9556 (2000)).

In addition to the mammalian chemokine receptors, the Decoy receptorsCCX—CKR, D6 and DARC/Duffy as well proteins expressed by mammaliancytomegaloviruses, herpes viruses and poxviruses, exhibit bindingproperties of chemokine receptors (reviewed by Wells and Schwartz, Curr.Opin. Biotech., 8, 741-748 (1997); Comerford, Bioessays., 29(3):237-47(2007)). Human CC chemokines, such as RANTES and MCP-3, can cause rapidmobilization of calcium via these virally encoded receptors. Receptorexpression may be permissive for infection by allowing for thesubversion of normal immune system surveillance and response toinfection. Additionally, human chemokine receptors, such as CXCR-4,CCR2, CCR3, CCR5 and CCR8, can act as co receptors for the infection ofmammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis, Grave's disease, chronicobstructive pulmonary disease, and atherosclerosis. For example, thechemokine receptor CCR3 is expressed among others on eosinophils,basophils, TH2 cells, alveolar macrophages, mast cells, epithelialcells, microglia cells, astrocytes and fibroblasts. CCR3 plays a pivotalrole in attracting eosinophils to sites of allergic inflammation and insubsequently activating these cells. The chemokine ligands for CCR3induce a rapid increase in intracellular calcium concentration,increased GTP exchange of G-proteins, increased ERK phosphorylation,enhanced receptor internalization, eosinophil shape change, increasedexpression of cellular adhesion molecules, cellular degranulation, andthe promotion of migration. Accordingly, agents that inhibit chemokinereceptors would be useful in such disorders and diseases. In addition,agents that inhibit chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

Therefore, CCR3 is an important target and antagonism of CCR3 is likelyto be effective in the treatment of inflammatory, eosinophilic,immunoregulatory and infectious disorders and diseases (Wegmann, Am JRespir Cell Mol. Biol., 36(1):61-67 (2007); Fryer J Clin Invest.,116(1):228-236 (2006); De Lucca, Curr Opin Drug Discov Devel.,9(4):516-524 (2006)

The compounds of the instant application are useful for manufacturing amedicament for the prevention and/or treatment of diseases wherein theactivity of a CCR3-receptor is involved. Preferred is the manufacturingof a medicament for the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases ofthe respiratory or gastrointestinal complaints as well as inflammatorydiseases of the joints and allergic diseases of the nasopharynx, eyes,and skin, including asthma and allergic diseases, eosinophilic diseases,infection by pathogenic microbes (which, by definition, includesviruses), as well as autoimmune pathologies such as the rheumatoidarthritis and atherosclerosis.

The problem underlying the present invention was the provision of novelCCR3 antagonists, preferred with reduced side effects. It has been foundsurprisingly that substituted piperidines of formula 1 are highlysuitable as CCR3 antagonists, having less side effects, e.g. inhibitionof norepinephrine (NET), dopamine (DAT) or serotonin reuptaketransporters (5-HTT) as described by Watson P S, Bioorg MED Chem Lett.,16(21):5695-5699 (2006), or inhibition of 5HT2A, 5HT2C or Dopamine D2receptors as described by De Lucca, J Med Chem., 48(6):2194-2211 (2005),or inhibition of the hERG channel as described by De Lucca, Curr OpinDrug Discov Devel., 9(4):516-524 (2006), or inhibition of the alpha1Badrenergic receptor.

DETAILED DESCRIPTION OF THE INVENTION

Embodiment of the present invention are compounds of formula 1, wherein

-   A is CH₂, O or N—C₁₋₆-alkyl;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   NH—C₃₋₆-cycloalkyl, whereas optionally one carbon atom is        replaced by a nitrogen atom, whereas the ring is optionally        substituted with one or two residues selected from the group        consisting of C₁₋₆-alkyl, O—C₁₋₆alkyl, NHSO₂-phenyl,        NHCONH-phenyl, halogen, CN, SO₂—C₁₋₆-alkyl, COO—C₁₋₆-alkyl;    -   a C_(9 or 10)-bicyclic-ring, whereas one or two carbon atoms are        replaced by nitrogen atoms and the ring system is bound via a        nitrogen atom to the basic structure of formula 1 and whereas        the ring system is optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        COO—C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl, NO₂, halogen, CN,        NHSO₂—C₁₋₆-alkyl, methoxy-phenyl;    -   a group selected from NHCH(pyridinyl)CH₂COO—C₁₋₆-alkyl,        NHCH(CH₂O—C₁₋₆-alkyl)benzoimidazolyl, optionally substituted        with halogen or CN;    -   or 1-aminocyclopentyl, optionally substituted with        methyl-oxadiazole    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,        C₂₋₆-alkenylene-OH, C₂₋₆-alkynylene-OH, CH₂CON(C₁₋₆-alkyl)₂,        CH₂NHCONH—C₃₋₆-cycloalkyl, CN, CO-pyridinyl,        CONR^(1.1.1)R^(1.1.2), COO—C₁₋₆-alkyl,        N(SO₂—C₁₋₆-alkyl)(CH₂CON(C₁₋₄-alky)₂) O—C₁₋₆-alkyl, O-pyridinyl,        SO₂—C₁₋₆-alkyl, SO₂—C₁₋₆-alkylen-OH, SO₂—C₃₋₆-cycloalkyl,        SO₂-piperidinyl, SO₂NH—C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂, halogen,        CN, CO-morpholinyl, CH₂-pyridinyl or a heterocyclic ring        optionally substituted with one or two residues selected from        the group consisting of C₁₋₆-alkyl, NHC₁₋₆-alkyl and ═O;        -   R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl,            CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,            C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₆-alkylen-OH or            thiadiazolyl, optionally substituted with C₁₋₆-alkyl;        -   R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one N or O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of C₁₋₆-alkyl, C₁₋₄-alkylene-OH,            OH, ═O;        -   or    -   R^(1.1) is phenyl, wherein two adjacent residues are together        forming a five- or six-membered carbocyclic aromatic or        non-aromatic ring, optionally containing independently from each        other one or two N, S, or SO₂, replacing a carbon atom of the        ring, wherein the ring is optionally substituted with C₁₋₄-alkyl        or ═O;    -   R^(1.2) is selected from        -   heteroaryl, optionally substituted with one or two residues            selected from the group consisting of C₁₋₆-alkyl,            C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,            CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2), COR^(1.2.3),            COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,            SO₂N(C₁₋₆-alkyl)₂ or heteroaryl optionally substituted with            one or two residues selected from the group consisting of            C₁₋₆-alkyl;        -   heteroaryl, optionally substituted with a five- or            six-membered carbocyclic non-aromatic ring containing            independently from each other two N, O, S, or SO₂, replacing            a carbon atom of the ring;        -   a aromatic or non-aromatic C_(9 or 10)-bicyclic-ring,            whereas one or two carbon atoms are replaced by N, O or S            each optionally substituted with one or two residues            selected from the group consisting of N(C₁₋₆-alkyl)₂,            CONH—C₁₋₆-alkyl, ═O;        -   a heterocyclic non-aromatic ring, optionally substituted            with pyridinyl;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCO—C₁₋₆-alkyl,        -   R^(1.2.1) H, C₁₋₆-alkylene-C₃₋₆-cycloalkyl,            C₁₋₄-alkylene-phenyl, C₁₋₄-alkylene-furanyl,            C₃₋₆-cycloalkyl, C₁₋₄-alkylene-O—C₁₋₄-alkyl, C₁₋₆-haloalkyl            or a five- or six-membered carbocyclic non-aromatic ring,            optionally containing independently from each other one or            two N, O, S, or SO₂, replacing a carbon atom of the ring,            optionally substituted with 4-cyclopropylmethyl-piperazinyl        -   R^(1.2.2) H, C₁₋₆-alkyl;        -   R^(1.2.3) a five- or six-membered carbocyclic non-aromatic            ring, optionally containing independently from each other            one or two N, O, S, or SO₂, replacing a carbon atom of the            ring;    -   R^(1.3) is selected from phenyl, heteroaryl or indolyl, each        optionally substituted with one or two residues selected from        the group consisting of C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        O—C₁₋₆-haloalkyl, phenyl, heteroaryl;-   R² is selected from the group consisting of C₁₋₆-alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆-alkylene-heteroaryl; each    optionally substituted with one, two or three residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₆-alkyl;-   R⁴ is H, C₁₋₆-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,        C₂₋₆-alkenylene-OH, C₂₋₆-alkynylene-OH, CH₂CON(C₁₋₆-alkyl)₂,        CH₂NHCONH—C₃₋₆-cycloalkyl, CN, CO-pyridinyl,        CONR^(1.1.1)R^(1.1.2), COO—C₁₋₆-alkyl,        N(SO₂—C₁₋₆-alkyl)(CH₂CON(C₁₋₄-alky)₂) O—C₁₋₆-alkyl, O-pyridinyl,        SO₂—C₁₋₆-alkyl, SO₂—C₁₋₆-alkylen-OH, SO₂—C₃₋₆-cycloalkyl,        SO₂-piperidinyl, SO₂NH—C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂, halogen,        CN, CO-morpholinyl, CH₂-pyridinyl or a heterocyclic ring        optionally substituted with one or two residues selected from        the group consisting of C₁₋₆-alkyl, NHC₁₋₆-alkyl, ═O;        -   R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl,            CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,            C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₆-alkylen-OH or            thiadiazolyl, optionally substituted with C₁₋₆-alkyl;        -   R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one N or O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of C₁₋₆-alkyl, C₁₋₄-alkylene-OH,            OH, ═O;        -   or    -   R^(1.1) is phenyl, wherein two adjacent residues are together        forming a five- or six-membered carbocyclic aromatic or        non-aromatic ring, optionally containing independently from each        other one or two N, S, or SO₂, replacing a carbon atom of the        ring, wherein the ring is optionally substituted with C₁₋₄-alkyl        or ═O;    -   R^(1.2) is selected from        -   heteroaryl, optionally substituted with one or two residues            selected from the group consisting of C₁₋₆-alkyl,            C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,            CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2), COR^(1.2.3),            COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,            SO₂N(C₁₋₄-alkyl)₂ or heteroaryl optionally substituted with            one or two residues selected from the group consisting of            C₁₋₆-alkyl;        -   heteroaryl, optionally substituted with a five- or            six-membered carbocyclic non-aromatic ring containing            independently from each other two N, O, S, or SO₂, replacing            a carbon atom of the ring;        -   R^(1.2.1) C₁₋₆-alkylene-C₃₋₆-cycloalkyl,            C₁₋₄-alkylene-phenyl, C₁₋₄-alkylene-furanyl,            C₃₋₆-cycloalkyl, C₁₋₄-alkylene-O—C₁₋₄-alkyl, C₁₋₆-haloalkyl            or a five- or six-membered carbocyclic non-aromatic ring,            optionally containing independently from each other one or            two N, O, S, or SO₂, replacing a carbon atom of the ring,            optionally substituted with 4-cyclopropylmethyl-piperazinyl        -   R^(1.2.2) H, C₁₋₆-alkyl;        -   R^(1.2.3) a five- or six-membered carbocyclic non-aromatic            ring, optionally containing independently from each other            one or two N, O, S, or SO₂, replacing a carbon atom of the            ring;    -   R^(1.3) is selected from phenyl, heteroaryl or indolyl, each        optionally substituted with one or two residues selected from        the group consisting of C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        O—C₁₋₆-haloalkyl, phenyl, heteroaryl; preferably R^(1.3) is        selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        C₁₋₆-alkyl, C₃₋₆-cycloalkyl, O—C₁₋₆alkyl, O—C₁₋₆-haloalkyl,        phenyl, pyrrolidinyl;-   R² is selected from the group consisting of C₁₋₆-alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆-alkylene-thiophenyl; each    optionally substituted with one, two or three residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆.    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,        C₂₋₆-alkenylene-OH, C₂₋₆-alkynylene-OH, CH₂CON(C₁₋₆-alkyl)₂,        CH₂NHCONH—C₃₋₆-cycloalkyl, CN, CO-pyridinyl,        CONR^(1.1.1)R^(1.1.2), COO—C₁₋₆-alkyl,        N(SO₂—C₁₋₆-alkyl)(CH₂CON(C₁₋₄-alkyl)₂) O—C₁₋₆-alkyl,        O-pyridinyl, SO₂—C₁₋₆-alkyl, SO₂—C₁₋₆-alkylen-OH,        SO₂—C₃₋₆-cycloalkyl, SO₂-piperidinyl, SO₂NH—C₁₋₆-alkyl,        SO₂N(C₁₋₆-alkyl)₂, halogen, CN, CO-morpholinyl, CH₂-pyridinyl or        a heterocyclic ring optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        NHC₁₋₆-alkyl, ═O;        -   R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl,            CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,            C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₆-alkylen-OH or            thiadiazolyl, optionally substituted with C₁₋₆-alkyl;        -   R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one N or O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of C₁₋₆-alkyl, C₁₋₄-alkylene-OH,            OH, ═O;        -   or    -   R^(1.1) is phenyl, wherein two adjacent residues are together        forming a five- or six-membered carbocyclic aromatic or        non-aromatic ring, optionally containing independently from each        other one or two N, S, or SO₂, replacing a carbon atom of the        ring, wherein the ring is optionally substituted with C₁₋₄-alkyl        or ═O;-   R² is selected from the group consisting of C₁₋₆alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆alkylene-thiophenyl; each optionally    substituted with one, two or three residues selected from the group    consisting of C₁₋₆-alkyl, C₁₋₆haloalkyl, O—C₁₋₆alkyl,    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHR^(1.2), NMeR^(1.2);    -   R^(1.2) is selected from        -   heteroaryl, optionally substituted with one or two residues            selected from the group consisting of C₁₋₆-alkyl,            C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,            CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2), COR^(1.2.3),            COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,            SO₂N(C₁₋₄-alkyl)₂ or heteroaryl optionally substituted with            one or two residues selected from the group consisting of            C₁₋₆-alkyl;        -   heteroaryl, optionally substituted with a five- or            six-membered carbocyclic non-aromatic ring containing            independently from each other two N, O, S, or SO₂, replacing            a carbon atom of the ring;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of            N(C₁₋₆-alkyl)₂, CONH—C₁₋₆-alkyl, ═O;        -   piperidinyl, optionally substituted with pyridinyl;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCO—C₁₋₆-alkyl,        -   R^(1.2.1) H, C₁₋₆-alkylene-C₃₋₆-cycloalkyl,            C₁₋₄-alkylene-phenyl, C₁₋₄-alkylene-furanyl,            C₃₋₆-cycloalkyl, C₁₋₄-alkylene-O—C₁₋₄-alkyl, C₁₋₆-haloalkyl            or a five- or six-membered carbocyclic non-aromatic ring,            optionally containing independently from each other one or            two N, O, S, or SO₂, replacing a carbon atom of the ring,            optionally substituted with 4-cyclopropylmethyl-piperazinyl        -   R^(1.2.2) H, C₁₋₆-alkyl;        -   R^(1.2.3) a five- or six-membered carbocyclic non-aromatic            ring, optionally containing independently from each other            one or two N, O, S, or SO₂, replacing a carbon atom of the            ring;-   R² is selected from the group consisting of C₁₋₆-alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆-alkylene-thiophenyl; each    optionally substituted with one, two or three residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHR^(1.2), NMeR^(1.2);    -   R^(1.2) is selected from        -   heteroaryl, optionally substituted with one or two residues            selected from the group consisting of C₁₋₆-alkyl,            C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,            CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2), COR^(1.2.3),            COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,            SO₂N(C₁₋₄-alkyl)₂ or heteroaryl optionally substituted with            one or two residues selected from the group consisting of            C₁₋₆-alkyl;        -   heteroaryl, optionally substituted with a five- or            six-membered carbocyclic non-aromatic ring containing            independently from each other two N, O, S, or SO₂, replacing            a carbon atom of the ring;        -   R^(1.2.1) H, C₁₋₆-alkyl, C₁₋₆-alkylene-C₃₋₆-cycloalkyl,            C₁₋₄-alkylene-phenyl, C₁₋₄-alkylene-furanyl,            C₃₋₆-cycloalkyl, C₁₋₄-alkylene-O—C₁₋₄-alkyl, C₁₋₆-haloalkyl            or a five- or six-membered carbocyclic non-aromatic ring,            optionally containing independently from each other one or            two N, O, S, or SO₂, replacing a carbon atom of the ring,            optionally substituted with 4-cyclopropylmethyl-piperazinyl        -   R1.2.2 H, C₁₋₆-alkyl;        -   R^(1.2.3) a five- or six-membered carbocyclic non-aromatic            ring, optionally containing independently from each other            one or two N, O, S, or SO₂, replacing a carbon atom of the            ring;-   R² is selected from the group consisting of C₁₋₆-alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆-alkylene-thiophenyl; each    optionally substituted with one, two or three residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl,    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHCH₂—R^(1.3);    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each optionally        substituted with one or two residues selected from the group        consisting of C₁₋₆-alkyl, C₃₋₆-cycloalkyl, O—C₁₋₆-alkyl,        O—C₁₋₆-haloalkyl, phenyl, pyrrolidinyl;-   R² is selected from the group consisting of C₁₋₆-alkylene-phenyl,    C₁₋₆-alkylene-naphthyl, and C₁₋₆-alkylene-thiophenyl; each    optionally substituted with one, two or three residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,    O—C₁₋₆-haloalkyl, halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or N—C₁₋₄-alkyl;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   NH—C₃₋₆-cycloalkyl, whereas optionally one carbon atom is        replaced by a nitrogen atom, whereas the ring is optionally        substituted with one or two residues selected from the group        consisting of C₁₋₆alkyl, O—C₁₋₆alkyl, NHSO₂-phenyl,        NHCONH-phenyl, halogen, CN, SO₂—C₁₋₆-alkyl, COO—C₁₋₆-alkyl;    -   a C_(9 or 10)-bicyclic-ring, whereas one or two carbon atoms are        replaced by nitrogen atoms and the ring system is bound via a        nitrogen atom to the basic structure of formula 1 and whereas        the ring system is optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        COO—C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆alkyl, NO₂, halogen, CN,        NHSO₂—C₁₋₆-alkyl, m-methoxyphenyl;    -   a group selected from NHCH(pyridinyl)CH₂COO—C₁₋₆-alkyl,        NHCH(CH₂O—C₁₋₆-alkyl)benzoimidazolyl, optionally substituted        with Cl;    -   or 1-aminocyclopentyl, optionally substituted with        methyl-oxadiazolyl;    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₆-alkyl,        C₁₋₆-haloalkyl, CH₂CON(C₁₋₆-alkyl)₂, CH₂NHCONH—C₃₋₆-cycloalkyl,        CN, CONR^(1.1.1)R^(1.1.2), COO—C₁₋₆-alkyl, O—C₁₋₆-alkyl,        SO₂—C₁₋₆-alkyl, SO₂—C₁₋₆-alkylen-OH, SO₂—C₃₋₆-cycloalkyl,        SO₂-piperidinyl, SO₂NH—C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂, halogen,        CN, CO-morpholinyl, CH₂-pyridinyl or a heterocyclic ring        optionally substituted with one or two residues selected from        the group consisting of C₁₋₆-alkyl, NHC₁₋₆-alkyl, ═O;        -   R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl,            CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,            C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₆-alkylen-OH or            thiadiazolyl, optionally substituted with C₁₋₆-alkyl;        -   R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH    -   R^(1.2) is selected from        -   heteroaryl, optionally substituted with one or two residues            selected from the group consisting of C₁₋₆-alkyl,            C₃₋₆-cycloalkyl, CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2),            COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,            CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally            substituted with one or two residues selected from the group            consisting of C₁₋₆-alkyl;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of            N(C₁₋₆-alkyl)₂, CONH—C₁₋₆-alkyl, ═O;        -   piperidinyl, optionally substituted with pyridinyl;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCO—C₁₋₆-alkyl,        -   R^(1.2.1) H, C₁₋₆-alkyl;        -   R^(1.2.2) H, C₁₋₆-alkyl;    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        C₁₋₆-alkyl, C₃₋₆-cycloalkyl, O—C₁₋₆-alkyl, O—C₁₋₆-haloalkyl;-   R² is selected from C₁₋₆-alkylene-phenyl or C₁₋₆-alkylene-naphthyl,    both optionally substituted with one or two residues selected from    the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,    O—C₁₋₆-haloalkyl, halogen; or CH₂-thiophenyl, optionally substituted    with one or two residues selected from the group consisting of    halogen;-   R³ is H, C₁₋₄-alkyl;-   R⁴ is H, C₁₋₄-alkyl;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   NH-cyclohexyl, optionally substituted with one or two residues        selected from the group consisting of C₁₋₄-alkyl, NHSO₂-phenyl,        NHCONH-phenyl, halogen;    -   NH-pyrrolidinyl, optionally substituted with one or two residues        selected from the group consisting of SO₂—C₁₋₄-alkyl,        COO—C₁₋₄-alkyl;    -   piperidinyl, optionally substituted with one or two residues        selected from the group consisting of NHSO₂—C₁₋₄-alkyl,        m-methoxyphenyl;    -   dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or        tetrahydro-isoquinolinyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₄-alkyl,        COO—C₁₋₄-alkyl, C₁₋₄-haloalkyl, NO₂, halogen;    -   a group selected from NHCH(pyridinyl)CH₂COO—C₁₋₄-alkyl,        NHCH(CH₂O—C₁₋₄-alkyl)-benzoimidazolyl, optionally substituted        with Cl;    -   or 1-aminocyclopentyl, optionally substituted with        methyl-oxadiazolyl;    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of C₁₋₄-alkyl,        C₁₋₄-haloalkyl, CH₂CON(C₁₋₄-alkyl)₂, CH₂NHCONH—C₃₋₆-cycloalkyl,        CN, CONR^(1.1.1)R^(1.1.2), COO—C₁₋₄-alkyl, O—C₁₋₄-alkyl,        SO₂—C₁₋₄-alkyl, SO₂—C₁₋₄-alkylen-OH, SO₂—C₃₋₆-cycloalkyl,        SO₂-piperidinyl, SO₂NH—C₁₋₄-alkyl, SO₂N(C₁₋₄-alkyl)₂, halogen,        CO-morpholinyl, CH₂-pyridinyl, or imidazolidinyl, piperidinyl,        oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,        oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally        substituted with one or two residues selected from the group        consisting of C₁₋₄-alkyl, NHC₁₋₄-alkyl, ═O;        -   R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₄-haloalkyl,            CH₂CON(C₁₋₄-alkyl)₂, CH₂CO-azetindinyl,            C₁₋₄-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₄-alkylen-OH or            thiadiazolyl, optionally substituted with C₁₋₄-alkyl;        -   R^(1.1.2) H, C₁₋₄-alkyl, SO₂C₁₋₄-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH    -   R^(1.2) is selected from        -   pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl,            thiazolyl, thiadiazolyl, optionally substituted with one or            two residues selected from the group consisting of            C₁₋₄-alkyl, C₃₋₆-cycloalkyl, CH₂COO—C₁₋₄-alkyl,            CONR^(1.2.1)R^(1.2.2), COO—C₁₋₄-alkyl, CONH₂, O—C₁₋₄-alkyl,            halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl,            triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each            optionally substituted with one or two residues selected            from the group consisting of C₁₋₄-alkyl;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of            N(C₁₋₄-alkyl)₂, CONH—C₁₋₄-alkyl, ═O;        -   piperidinyl, optionally substituted with pyridinyl;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCO—C₁₋₄-alkyl,        -   R^(1.2.1) H, C₁₋₄-alkyl;        -   R^(1.2.2) H, C₁₋₄-alkyl;    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        C₁₋₄-alkyl, C₃₋₆cycloalkyl, O—C₁₋₄-alkyl, O—C₁₋₄-haloalkyl;-   R² is selected from C₁₋₆-alkylene-phenyl or C₁₋₆alkylene-naphthyl,    both optionally substituted with one or two residues selected from    the group consisting of C₁₋₄-alkyl, C₁₋₄-haloalkyl,    O—C₁₋₄-haloalkyl, halogen; or CH₂-thiophenyl, optionally substituted    with one or two residues selected from the group consisting of    halogen;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   NH-piperidinyl, optionally substituted with pyridinyl;    -   NH-cyclohexyl, optionally substituted with one or two residues        selected from the group consisting of t-Bu, NHSO₂-phenyl,        NHCONH-phenyl, F;    -   NH-pyrrolidinyl, optionally substituted with one or two residues        selected from the group consisting of SO₂Me, COO-t-Bu;    -   piperidinyl, optionally substituted with one or two residues        selected from the group consisting of NHSO₂-n-Bu,        m-methoxyphenyl;    -   dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or        tetrahydro-isoquinolinyl, optionally substituted with one or two        residues selected from the group consisting of Me, COOMe, CF₃,        OMe, NO₂, F, Br;    -   a group selected from NHCH(pyridinyl)CH₂COOMe,        NHCH(CH₂OMe)-benzoimidazolyl, optionally substituted with Cl;    -   or 1-aminocyclopentyl, optionally substituted with        methyl-oxadiazolyl;    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, t-Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;        -   R^(1.1.1) H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr,            CH₂-t-Bu, CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂,            CH₂CO-azetindinyl, CH₂-cyclopropyl, CH₂-cyclobutyl,            CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH    -   R^(1.2) is selected from        -   pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl,            thiadiazolyl, optionally substituted with one or two            residues selected from the group consisting of Me, Et, Pr,            Bu, cyclopropyl, CH₂COOEt, CONR^(1.2.1)R^(1.2.2), COOMe,            COOEt, CONH₂, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or            pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl,            each optionally substituted Me;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of NMe₂,            CONHMe, ═O;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCOMe,        -   R^(1.2.1) H, Me;        -   R^(1.2.2) H, Me;    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, Et, Pr, cyclopentyl, OMe, OCHF₂;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1)    -   NHR^(1.2),    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, Pr, Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;        -   R^(1.1.1) H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-t-Bu,            CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,            CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH    -   R^(1.2) is selected from        -   pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl,            thiadiazolyl, optionally substituted with one or two            residues selected from the group consisting of Me, Et, Pr,            Bu, cyclopropyl, CH₂COOEt, CONR^(1.2.1)R^(1.2.2), COOMe,            COOEt, CONH₂, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or            pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl,            each optionally substituted Me;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of NMe₂,            CONHMe, ═O;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCOMe,        -   R^(1.2.1) H, Me;        -   R^(1.2.2) H, Me;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et-   R³ is H;-   R⁴ is H.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   is selected from    -   NHR^(1.1), NMeR^(1.1);    -   NHR^(1.2), NMeR^(1.2);    -   NHCH₂—R^(1.3);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, Pr, Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;        -   R^(1.1.1) H, Me, Et, Pr, Bu, cyclopropyl, CH₂—Pr, CH₂—Bu,            CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,            CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH    -   R^(1.2) is selected from        -   pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl,            thiadiazolyl, optionally substituted with one or two            residues selected from the group consisting of Me, Et, Pr,            Bu, cyclopropyl, CH₂COOEt, CONR^(1.2.1)R^(1.2.2), COOMe,            COOEt, CONH₂, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or            pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl,            each optionally substituted Me;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of NMe₂,            CONHMe, ═O;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCOMe,        -   R^(1.2.1) H, Me;        -   R^(1.2.2) H, Me;    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, Et, Pr, cyclopentyl, OMe, OCHF₂;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, t-Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;        -   R^(1.1.1) H, Me, Et, Bu, Pr, cyclopropyl, CH₂—Pr, CH₂—Bu,            CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,            CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et        -   or R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, t-Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;    -   R^(1.1.1) H, Me, Et, Bu, Pr, cyclopropyl, CH₂—Pr, CH₂—Bu,        CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,        CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,        CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or thiadiazolyl,        optionally substituted with Me;    -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et    -   or R^(1.1.1) and R^(1.1.2) together are forming a four-, five-        or six-membered carbocyclic ring, optionally containing one O,        replacing a carbon atom of the ring, optionally substituted with        one or two residues selected from the group consisting of CH₂OH;-   R² is defined as in table 1 shown below;-   R³ is H;-   R⁴ is H;

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, t-Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, CO-morpholinyl,        CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl,        pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,        thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, NHMe, ═O;        -   and R^(1.1.1) and R^(1.1.2) together are forming a four-,            five- or six-membered carbocyclic ring, optionally            containing one O, replacing a carbon atom of the ring,            optionally substituted with one or two residues selected            from the group consisting of CH₂OH;-   R² is defined as in table 1 shown below;-   R³ is H;-   R⁴ is H;

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, t-Bu,        CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, F, Cl;    -   R^(1.1.1) H, Me, Et, Bu, Pr, cyclopropyl, CH₂—Pr, CH₂—Bu,        CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,        CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,        CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or thiadiazolyl,        optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et-   R² is defined as in table 1 shown below;-   R³ is H;-   R⁴ is H;

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one or two        residues selected from the group consisting of SO₂Me,        SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl, SO₂-piperidinyl, SO₂NHEt,        SO₂NMeEt;        -   R^(1.1.1) H, Me, Et, Bu, Pr, cyclopropyl, CH₂—Pr, CH₂—Bu,            CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,            CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et-   R² is defined as in table 1 shown below;-   R³ is H;-   R⁴ is H;

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R^(1.1) is selected from    -   NHR^(1.1), NMeR^(1.1);    -   R^(1.1) is phenyl, optionally substituted with one residue        selected from the group consisting of Me, Et, t-Bu, CF₃,        CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2),        COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl,        SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl, and additionally with        one residue selected from the group consisting of        CO-morpholinyl, CH₂-pyridinyl, or imidazolidinyl, piperidinyl,        oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,        oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally        substituted with one or two residues selected from the group        consisting of Me, NHMe, ═O;        -   R^(1.1.1) H, Me, Et, Bu, Pr, cyclopropyl, CH₂—Pr, CH₂—Bu,            CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,            CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl,            CH₂-tetrahydrofuranyl, CH₂-furanyl, CH₂CH₂OH or            thiadiazolyl, optionally substituted with Me;        -   R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et-   R² is defined as in table 1 shown below;-   R³ is H;-   R⁴ is H;

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.2), NMeR^(1.2);    -   R^(1.2) is selected from        -   pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl,            thiazolyl, thiadiazolyl, optionally substituted with one or            two residues selected from the group consisting of Me, Et,            Pr, Bu, cyclopropyl, CH₂COOEt, CONR^(1.2.1)R^(1.2.2), COOMe,            COOEt, CONH₂, OMe, Cl, Br CO-pyrrolidinyl, CO-morpholinyl or            pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl,            each optionally substituted Me;        -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,            tetrahydro-quinolinyl, each optionally substituted with one            or two residues selected from the group consisting of NMe₂,            CONHMe, ═O;        -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted            with NHCOMe,        -   R^(1.2.1) H, Me;        -   R^(1.2.2) H, Me;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHR^(1.2), NMeR^(1.2);    -   R^(1.2) is selected from pyridinyl, pyridazinyl, pyrrolyl,        pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally        substituted with one or two residues selected from the group        consisting of Me, Et, n-Pr, i-Pr, Bu, cyclopropyl, CH₂COOEt,        CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe, Cl, Br        CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl,        tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted        Me;        -   R^(1.2.1) H, Me;        -   R^(1.2.2) H, Me;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NHCH₂—R^(1.3);    -   R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl,        pyrimidinyl, indolyl or oxadiazolyl, each optionally substituted        with one or two residues selected from the group consisting of        Me, Et, Pr, cyclopentyl, OMe, OCHF₂;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from    -   NH-piperidinyl, optionally substituted with pyridinyl;    -   NH-cyclohexyl, optionally substituted with one or two residues        selected from the group consisting of t-Bu, NHSO₂-phenyl,        NHCONH-phenyl, F;    -   NH-pyrrolidinyl, optionally substituted with one or two residues        selected from the group consisting of SO₂Me, COO-t-Bu;    -   piperidinyl, optionally substituted with one or two residues        selected from the group consisting of NHSO₂-n-Bu,        m-methoxyphenyl;    -   dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl or        tetrahydro-isoquinolinyl, optionally substituted with one or two        residues selected from the group consisting of Me, COOMe, CF₃,        OMe, NO₂, F, Br;    -   a group selected from NHCH(pyridinyl)CH₂COOMe,        NHCH(CH₂OMe)-benzoimidazolyl, optionally substituted with Cl;    -   or 1-aminocyclopentyl, optionally substituted with        Methyl-Oxadiazolyl;-   R² is selected from CH₂-phenyl or CH₂-naphthyl, both optionally    substituted with one or two residues selected from the group    consisting of CH₃, CF₃, OCF₃, F, Cl, Br, Et; or CH₂-thiophenyl,    optionally substituted with one or two residues selected from the    group consisting of Cl, Br;-   R³ is H;-   R⁴ is H;    -   or R^(3 and R) ⁴ together are forming a CH₂ CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);R² is defined as in table 1 shown below; R³ is H; R⁴ is and R^(1.2) isselected from

-   -   pyridinyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, i-Pr, n-Bu,        cyclopropyl, CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe,        Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl,        tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted        Me;    -   pyrrolyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, COOMe, COOEt;    -   pyrazolyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, cyclopropyl,        COOEt, CO-pyrrolidinyl;    -   isoxazolyl, optionally substituted with one or two residues        selected from the group consisting of t-Bu, COOEt;    -   thiazolyl, optionally substituted with one or two residues        selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe,        COOEt, CH₂COOEt, CONR^(1.2.1)R^(1.2.2);    -   thiadiazolyl, optionally substituted with one or two residues        selected from the group consisting of COOEt;    -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,        tetrahydro-quinolinyl, each optionally substituted with one or        two residues selected from the group consisting of NMe₂, CONHMe,        ═O;    -   4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with        NHCOMe,

-   and

-   R^(1.2.1) is H or Me;

-   R^(1.2.2) is H or Me.

Another embodiment of the present invention are compounds of formula 1,wherein A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);R² is defined as in table 1 shown below; R³ is H; R⁴ is and R^(1.2) isselected from

-   -   pyridinyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, i-Pr, n-Bu,        CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe, Cl, Br;    -   pyrrolyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, COOMe, COOEt;    -   pyrazolyl, optionally substituted with one or two residues        selected from the group consisting of Me, Et, cyclopropyl,        COOEt, CO-pyrrolidinyl;    -   isoxazolyl, optionally substituted with one or two residues        selected from the group consisting of t-Bu, COOEt;    -   thiazolyl, optionally substituted with one or two residues        selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe,        COOEt, CONR^(1.2.1)R^(1.2.2);    -   thiadiazolyl, optionally substituted with one or two residues        selected from the group consisting of COOEt;    -   benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,        tetrahydro-quinolinyl, each optionally substituted with one or        two residues selected from the group consisting of NMe₂, CONHMe,        ═O;

-   and

-   R^(1.2.1) is H or Me;

-   R^(1.2.2) is H or Me.

Another embodiment of the present invention are compounds of formula 1,wherein

-   -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is pyridinyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, i-Pr,        n-Bu, CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe, Cl, Br;        R^(1.2), is H or Me and R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is pyrrolyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et, COOMe,        COOEt; R^(1.2.1) is H or Me and R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is pyrazolyl, optionally substituted with one or two        residues selected from the group consisting of Me, Et,        cyclopropyl, COOEt, CO-pyrrolidinyl; R^(1.2.1) is H or Me and        R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is isoxazolyl, optionally substituted with one or two        residues selected from the group consisting of t-Bu, COOE;        R^(1.2.1) is H or Me and R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is thiazolyl, optionally substituted with one or two        residues selected from the group consisting of Me, n-Pr, i-Pr,        Bu, COOMe, COOEt, CONR^(1.2.1)R^(1.2.2); R^(1.2.1) is H or Me        and R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is thiadiazolyl, optionally substituted with one or two        residues selected from the group consisting of COOEt; R^(1.2.1)        is H or Me and R^(1.2.2) is H or Me.    -   A is CH₂, O or NMe, R¹ is selected from NHR^(1.2), NMeR^(1.2);        R² is defined as in table 1 shown below; R³ is H; R⁴ is H;        R^(1.2) is benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,        tetrahydro-quinolinyl, each optionally substituted with one or        two residues selected from the group consisting of NMe₂, CONHMe,        ═O; R^(1.2.1) is H or Me and R^(1.2.2) is H or Me.

Another embodiment of the present invention are compounds of formula 1,wherein all groups are defined as above except R^(1.3) is selected from

-   -   phenyl, optionally substituted with OCHF₂;    -   pyrazolyl, optionally substituted with Me or Et;    -   isoxazolyl, optionally substituted with Pr;    -   pyrimidinyl, optionally substituted with two OMe;    -   indolyl;    -   oxadiazolyl, optionally substituted with cyclopentyl.

Another embodiment of the present invention are compounds of formula 1,wherein all groups are defined as above except A is CH₂.

Another embodiment of the present invention are compounds of formula 1,wherein all groups are defined as above except A is O.

Another embodiment of the present invention are compounds of formula 1,wherein all groups are defined as above except A is NMe.

Another embodiment of the present invention are compounds of formula 1,wherein

-   A is CH₂, O or NMe;-   R¹ is selected from

-   R³ is H;-   R⁴ is H;    -   or R³ and R⁴ together are forming a CH₂—CH₂ group.

Another embodiment of the present invention are compounds of formula 1,wherein A is defined as above; R³ is H; R⁴ is H; and R² is defined as intable 1 shown below; and R¹ is selected from

Another embodiment of the present invention are compounds of formula 1,wherein A is defined as above; R³ is H; R⁴ is H; and R² is defined as intable 1 shown below; and R¹ is selected from

Another embodiment of the present invention are compounds of formula 1,wherein A is defined as above; R³ is H; R⁴ is H; and R² is defined as intable 1 shown below; R¹ is selected from

Another embodiment of the present invention are compounds of formula 1,wherein A is defined as above; R³ is H; R⁴ is H; and R² is defined as intable 1 shown below; R¹ is selected from

TABLE 1 R² is defined as one of the groups shown below in thedefinitions 1 to 4: Definition 1

Definition 2

Definition 3

Definition 4

Definition 5

Definition 6

Definition 7

Definition 8

Definition 9

Definition 10

A further embodiment of the invention are compounds of formula 1,wherein the compounds of formula 1 are present in the form of theindividual optical isomers, mixtures of the individual enantiomers orracemates, preferably in the form of the enantiomerically purecompounds. Especially preferred is the R-enantiomer of the compounds offormula 1 which is the following formula R-1

A further embodiment of the invention are compounds of formula 1,wherein the compounds of formula 1 are present in the form of the acidaddition salts thereof with pharmacologically acceptable acids as wellas optionally in the form of the solvates and/or hydrates.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, —C1-6 alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named group is theradical attachment point, for example, “thioalkyl” means a monovalentradical of the formula HS-Alk-. Unless otherwise specified below,conventional definitions of terms control and conventional stable atomvalences are presumed and achieved in all formulas and groups.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers, of a chemical structure or compound isintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds. For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, Succinate, Sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl Sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,P-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

By the term heterocyclic rings (“het”) are meant five-, six- orseven-membered, saturated or unsaturated heterocyclic rings or 5-10membered, bicyclic hetero rings which may contain one, two or threeheteroatoms, selected from among oxygen, sulphur and nitrogen; the ringmay be linked to the molecule by a carbon atom or, if present, by anitrogen atom. The following are examples of five-, six- orseven-membered, saturated or unsaturated heterocyclic rings:

Unless stated otherwise, a heterocyclic ring may be provided with a ketogroup. Examples include:

Examples of 5-10-membered bicyclic hetero rings are pyrrolizine, indole,indolizine, isoindole, indazole, purine, quinoline, isoquinoline,benzimidazole, benzofurane, benzopyrane, benzothiazole,benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

Although the term heterocyclic rings includes heterocyclic aromaticgroups, the term heterocyclic aromatic groups (“hetaryl”) denotes five-or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclichetaryl rings which may contain one, two or three heteroatoms, selectedfrom among oxygen, sulphur and nitrogen, which contain sufficientconjugated double bonds that an aromatic system is formed. The ring maybe linked to the molecule through a carbon atom or if present through anitrogen atom. The following are examples of five- or six-memberedheterocyclic aromatic groups:

Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine,indole, indolizine, isoindole, indazole, purine, quinoline,isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole,benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

The term “halogen” as used herein means a halogen substituent selectedfrom fluoro, chloro, bromo or iodo.

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples of these include: methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et,n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for theabove-mentioned groups. Unless stated otherwise, the definitions propyl,butyl, pentyl and hexyl include all the possible isomeric forms of thegroups in question. Thus, for example, propyl includes n-propyl andiso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groupswith 1 to 4 carbon atoms are preferred. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene or hexylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene and hexylene also include allthe possible isomeric forms of the relevant groups with the same numberof carbons. Thus for example propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

The term “C₂₋₆-alkenyl” (including those which are part of other groups)denotes branched and unbranched alkenyl groups with 2 to 6 carbon atomsand the term “C₂₋₄-alkenyl” denotes branched and unbranched alkenylgroups with 2 to 4 carbon atoms, provided that they have at least onedouble bond. Preferred are alkenyl groups with 2 to 4 carbon atoms.Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, orhexenyl. Unless otherwise stated, the definitions propenyl, butenyl,pentenyl and hexenyl include all possible isomeric forms of the groupsin question. Thus, for example, propenyl includes 1-propenyl and2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl,1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethenylene,propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus, for example, propenyl alsoincludes 1-methylethenylene and butenylene includes 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene.

By the term “C₂₋₆alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl and hexynyl include all the possible isomeric forms of therespective groups. Thus, for example, propynyl includes 1-propynyl and2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethynylene,propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

The term “C₃₋₆cycloalkyl” (including those which are part of othergroups) as used herein means cyclic alkyl groups with 3 to 8 carbonatoms, preferred are cyclic alkyl groups with 5 to 6 carbon atoms.Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms wherein one or more hydrogen atoms are replaced by ahalogen atom selected from among fluorine, chlorine or bromine,preferably fluorine and chlorine, particularly preferably fluorine. Bythe term “C₁₋₄-haloalkyl” are meant correspondingly branched andunbranched alkyl groups with 1 to 4 carbon atoms, wherein one or morehydrogen atoms are replaced analogously to what was stated above.C₁₋₄-haloalkyl is preferred. Examples include: CH₂F, CHF₂, CF₃,

EXAMPLES S. General Synthesis Procedures for Examples

The examples of the present invention are synthesized according to thefollowing general scheme:

General Synthesis Scheme:

where “building block” and “reaction partner” are defined for theprocedures A-G below in which A, R¹, R², R³ and R⁴ are defined as above.In case a building block or reaction partner is not commerciallyavailable, its synthesis is described below, commencing from acommercially available staring material, and where necessary, involvingintermediate(s), “I”.

The term “linker” is used to mean a chemical moiety whose definition isrestricted to that of R1 and is able to bear the specific functionalgroup as stated in order to undergo the reaction of the procedure. Inprocedure E, the synthesis starts from intermediate I12.2 which definesthe “building block”. In procedure G, the synthesis starts from example181 or 194 which define the “building block”

S.1. Procedures A-G

building block A1-A8

building block B1-B20

building block C1

building block D1-D2

I12.2 (see synthesis of building block A7)

building block F1-F3

example 181 or 194

S.2. Building Block Syntheses S.2.1 Synthesis of Building Blocks ofFormula A Synthesis of Building Blocks A1-A4 Synthesis of Building BlockA1

4-Chloro-3-methyl benzylbromide (20 g) [synthesized according toliterature: J. L. Kelley, J. A. Linn, J. W. T. Selway, J. Med. Chem.1989, 32(8), 1757-1763], 4-Piperidone (22 g), K₂CO₃ (26 g) inacetonitrile (300 ml) was heated at 50° C. for 14 h. The suspension wasfiltered and the filtrate concentrated in vacuum. The residue waspurified by flash chromatography (cyclohexane/EtOAc 1:1) to yield 17.4 gof intermediate I1.

Intermediate I1 (10 g) and D-H-Glu(O^(t)Bu)-OMe (10.8 g) was dissolvedin DMF (200 ml) and HOAc (5 ml). Then molecular sieve (1.0 g, 4

, powder) was added and the suspension was stirred overnight. Sodiumtriacetoxyborohydride (37.5 g) was added and the suspension stirreduntil complete conversion of the intermediate formed imine was observed.A basic pH was achieved by slow addition (foam formation!) of aqueousNaHCO₃ solution before additional water and DCM (500 mL) was added. Theorganic phase was separated and the water phase extracted with DCM (500ml). The organic phase was washed with brine, dried and concentrated invacuum to yield 19.5 g (74% purity) of intermediate I2.

Intermediate I2 (19.5 g, 74% purity) was dissolved in DCM (40 ml) andtrifluoroacetic acid (20 ml, TFA). The solution was stirred at 25° C.for 14 h before additional 40 ml TFA was added and the solutioncontinued stirring for further 7 h. The reaction mixture was thenconcentrated in vacuum, dissolved in toluene and concentrated again toprovide 29.5 g (purity 55%) of intermediate I3.

Intermediate I3 (29 g, purity 55%) was dissolved in DCM (100 ml) andDIPEA (22 ml). TBTU (15 g) was added and the solution was stirred for 30min. Then DCM (150 ml), water (100 ml) and saturated NaHCO₃ solution(100 ml) was added, the organic phase was separated and the water phaseextracted once with DCM (100 ml). The organic phase was dried andconcentrated to provide an oil which was then fractionated via reversedphase HPLC. The fractions containing the building block D1 wereconcentrated in vacuum, then a basic pH was adjusted with addition ofNaHCO₃ solution and the product was extracted with DCM to provide 8.1 gof intermediate I4.

Intermediate I4 (7 g) was dissolved in dioxane (50 ml). 2.5 M LiOHsolution (23 ml) and water (20 ml) was added and stirred at 25° C.overnight. The solution was acidified with aqueous 4N HCl and thenconcentrated in vacuum. The residue was dissolved in water, acetonitrileand a small amount of dioxane and lyophilised to provide 10.4 g solid(71% purity) of building block A1.

The building blocks were synthesized in analogy to acid A1:

Synthesis of Building Block A5

Acetic acid (5.7 ml) was added to a stirred suspension of(R)-2-amino-3-hydroxy-propionic acid methyl ester hydrochloride (5.98 g)and 4-oxo-piperidine-1-carboxylic acid benzyl ester (9.86 g) in DCM (382ml), and the conditions maintained for 70 min. To the resulting solutionwas then added sodium triacetoxyborohydride (28.51 g) in one portion,and the resulting suspension stirred overnight. The reaction mixture wasthen neutralized with a saturated aqueous solution of NaHCO₃, theorganic phase concentrated under reduced pressure to 60 ml, basified (pH8.5) with a saturated aqueous solution of NaHCO₃ and solid Na₂CO₃, MeOH(20 ml) was added and the phases separated, the aqueous one extractedtwice with a DCM: MeOH 3:1 mixture, the combined organic layers driedover Na₂SO₄ and evaporated to dryness to afford the product. The crudeI5 (17.58 g) was used in the next step without any further purification.

HPLC (R_(t))=2.48 min (method L)

Intermediate I5 (8 g, 35% content) was dissolved in THF (250 ml), thentriethylamine (3.48 ml), 4-dimethylamino pyridine (100 mg) and 1,1′carbonyldiimidazole (5.40 g) were added in sequence and the wholemixture stirred and refluxed under a nitrogen atmosphere for 48 h. Thesolvent and the volatiles were removed under reduced pressure and theresulting residue was taken up in EtOAc (150 ml), washed with water(3×100 ml), 10% citric acid (100 ml) and brine (100 ml). The organicphase was dried over Na₂SO₄, filtered and evaporated to dryness toafford product (6.6 g). This was purified twice (50 g Isolute® silicagel cartridge, eluting in the first purification with EtOAc/n-hexane80/20 and with 100% EtOAc in the second purification); the titlecompound (1.27 g).

HPLC (R_(t))=3.16 min (method G)

A suspension of 10% Pd/C (380 mg) in 50% aq. MeOH (4 ml) was added to astirred solution of intermediate I6 (3.79 g) in MeOH (28 ml). Themixture was then stirred under a positive pressure of hydrogen 14 h. Thereaction mixture was then filtered over Celite®, the cake washed withMeOH (4×10 ml) and the filtrate evaporated to dryness under reducedpressure to afford the desired free amine (2.2 g).

HPLC (R_(t))=0.51 min (method L)

Intermediate I7 (1.01 g) was suspended in dry acetonitrile (17.8 ml) ina nitrogen atmosphere; 4-bromomethyl-1-chloro-2-methyl-benzene (1.46 g)and K₂CO₃ (1.22 g) were added in sequence and the whole stirredovernight. The solvent was removed under reduced pressure, the residuewas taken up in EtOAc (50 ml), washed with water (1×30 ml), the layersseparated, the aqueous extracted with EtOAc (1×50 mL) and a 3:1 DCM:MeOHmixture (50 ml). The combined organic layers were dried over Na₂SO₄,filtered and evaporated to dryness. The residue was taken up in DCM andloaded on a 10 g-SCX cartridge eluting with DCM (50 ml), MeOH (50 ml),then ammonia (50 ml of a 0.5 M MeOH solution). Evaporation under reducedpressure of the MeOH and methanolic ammonia fractions afforded theproduct (895 mg) under vacuum, as a mixture of the methyl and benzylesters (4.5:1 by LC-MS).

The mixture of esters (895 mg) was suspended in THF (10 ml) and MeOH (2ml) was then added; the solution was ice chilled, LiOH*H2O (155 mg) andwater (10 ml) were added sequentially. The reaction was allowed to warmto room temperature and the resulting solution stirred for 70 min. Thereaction mixture was diluted with diethyl ether (10 ml), the phasesseparated; the aqueous was then acidified to pH 4 by dropwise additionof 6N HCl and freeze-dried overnight to afford the carboxylicacid-hydrochloride salt. The residue was suspended in a 4:1 DCM:iPrOHmixture, stirred at room temperature for 10 min, then filtered oncotton, the solvent evaporated to dryness under reduced pressure toafford the product (844 mg).

HPLC (Rt)=2.12 min (method H)

The following building blocks were synthesized in analogy to acid A5:

Synthesis of Building Block A7

To a stirred suspension of(R)-2-amino-3-tert-butoxycarbonylamino-propionic acid methyl esterhydrochloride (5.0 g) and 1-(4-chloro-3-methyl-benzyl)-piperidin-4-one(5.13 g) in DCM (200 ml), was added acetic acid (2.81 ml). After 70 minsodium triacetoxyborohydride (14.56 g) was added in one portion, and theresulting suspension stirred for 48 h. The reaction mixture was thendiluted with a saturated aqueous solution of NaHCO₃ (1×150 ml), the twolayers separated, the aqueous extracted with DCM (1×200 ml), thecombined organic layers dried over Na₂SO₄ and evaporated to dryness toafford the product. The crude was purified by flash chromatography(Biotage® SP1; 65M silica gel cartridge; gradient elution: DCM/MeOH/NH₃from 98/2/0.2 to 80/20/2 in 12 column volumes) affording 19 (7.0 g).

HPLC (R_(t))=10.03 min (method O)

To a stirred solution of Intermediate I9 (7.00 g in dioxane (50 ml), atroom temperature, was added HCl (39.78 ml of a 4N solution in1,4-dioxane) dropwise. MeOH (20 ml) was then added, and the reactionmixture stirred overnight. The solvents and the volatiles were removedunder reduced pressure, and the residue was triturated with diethylether affording product I10 (6.1 g). HPLC (R_(t))=1.89 min (method H)

Intermediate I10 (6.1 g) was suspended in THF (300 ml), thentriethylamine (12.41 ml), and 1,1′ carbonyldiimidazole (5.99 g) wereadded sequentially and the reaction refluxed under a nitrogen atmospherefor 100 min. The reaction mixture was allowed to cool down, filtered andthe filtrate evaporated under reduced pressure. and the residue waspurified by flash column chromatography (Biotage® SP1; 65M silica gelcartridge; gradient elution: DCM/MeOH/NH₃ from 98/2/0.2 to 80/20/2 in 12column volumes), affording a solid which was triturated with diethylether, to give I11 (1.85 g)

HPLC (R_(t))=8.37 min (method O)

A stirred solution of potassium t-butoxide in THF (7.38 ml, 1 M) at −50°C. under a nitrogen atmosphere was added dropwise to a solution ofintermediate I11 (1.80 g) in dry THF (45 ml). After 1 h, a solution ofiodomethane (0.46 ml) in dry THF (5 ml) was added dropwise to theresulting suspension, and the temperature was allowed to warm to 0° C.over 1 h. After this time, excess iodomethane was removed under reducedpressure at room temperature, the reaction was quenched with saturatedNH₄Cl(aq) (10 ml), the salts were filtered off and the filtrate dilutedwith EtOAc (30 mL) and brine (15 ml), the layers separated, the organicwashed once more with brine (15 ml), dried over Na₂SO₄ and evaporated todryness to afford a colourless oil, that was purified by flash columnchromatography (Biotage® SP1; 65M silica gel cartridge; gradientelution: DCM/MeOH from 98/2 to 80/20 in 15 column volumes), affordingproduct I12 (600 mg).

HPLC (R_(t))=8.92 min (method O)

Intermediate I12 (0.9 g) was dissolved in 4N HCl (30 ml) and refluxedfor 1 h. The solvent was evaporated to afford an oily residue that wastaken up in acetone and evaporated to dryness to afford a white solid,which was triturated with diisopropyl ether to afford building block A7(0.79 g).

HPLC (R_(t))=5.48 min (method O)

Building block A8 was synthesized in analogy to A7:

S.2.2. Synthesis of Building Blocks with Formula B Synthesis of BuildingBlock B1

To a stirred solution of example 87 (350 mg) in dioxane (10 ml) at 25°C. was added LiOH(aq) (0.7 ml, 2.5 M) and water (2 ml). After 3 h, 4NHCl (aq) solution was added to adjust the pH to 1-2. The solution wasconcentrated in vacuum, and water and acetonitrile added and the mixturelyophilised giving building block B 1. HPLC: 1.25 min (method D). Thiswas used without further purification in the next step.

Synthesis of Building Blocks B2-B15

The building blocks B2-B15 were synthesized in analogy to building blockB1 from the examples 88-92 (B2-B6), 110 (B7), 113 (B8), 111 (B9), 112(B10), 109 (B11), 216 (B12), 215 (B13), 195 (B14), 194 (B15)

Synthesis of Building Block B16

Step 1 3-Bromo-N-methyl-5-nitro-benzamide

To a solution of 3-bromo-5-nitro-benzoic acid (2.1 g) in DCM (50 ml) wasadded oxalylchloride (1.5 ml). 1 drop of DMF was added and the reactionstirred at room temperature for 2 h. The reaction was concentrated invacuum. This was dissolved in THF and added dropwise to a pre-cooled 2Msolution of methylamine in THF (22 ml) at 0° C. This was allowed to warmto room temperature and further stirred overnight. The reaction mixturewas filtered and the filtrate concentrated in vacuum. The residue wasdissolved in EtOAc and washed with water. The organic layer wasseparated, dried and concentrated in vacuum to leave the product (2.1g). Rt 1.37 min (method D).

Step 2 5-(3-Bromo-5-nitro-phenyl)-1-methyl-1H-tetrazole

To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15ml) at −15° C. was added triflic anhydride (0.6 ml) and the reactionstirred for 30 min. Sodium azide (226 mg) was added and the reactionallowed to warm to room temperature and stirred further overnight.NaHCO₃(aq) was added to neutralise the reaction and the mixtureextracted into EtOAc. The organic layer was separated, dried andconcentrated in vacuum and the residue purified by flash chromatography(9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg).R_(f)=0.51 (3:2 cyclohexane:EtOAc).

Step 3 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine

A solution of 5-(3-Bromo-5-nitro-phenyl)-1-methyl-1H-tetrazole (2.1 g)in EtOAc (100 ml) was hydrogenated on a H-cube® apparatus at 20° C.,room pressure with a flow rate of 1 ml/min using a Raney-Ni cartridge.After reaction completion, the mixture was concentrated in vacuum andtriturated with MeOH. The solid was filtered and further triturated andair-dried to give the title compound (290 mg). Rt 1.25 min (method D).

Step 41-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylicacid [3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide

To a solution of1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylicacid as DIPEA salt (2.6 g) in DMF (100 ml) was added DIPEA (2.1 g), andHATU (4 g). 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine (1.4 g)was added and the reaction stirred overnight at rt. The reaction mixturewas filtered and the filtrate partitioned between water and EtOAc. Theorganic layer was separated, dried and concentrated in vacuum and theresidue purified by flash chromatography (DCM:MeOH 100:0 to 95:5gradient) to give the title compound (400 mg). R_(f)=0.19 (95:5DCM:MeOH).

Step 53-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoicacid methyl ester

To a solution of1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylicacid [3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide (400 mg) inMeOH (20 ml) was added triethylamine (140 μl), DMF (5 ml), and[1,1′-bis(diphenylphosphino)-ferrocen]palladium (II) chloride (50 mg)and the reaction stirred for 2 d at 80° C. under a 3 bar CO atmosphere.The reaction mixture was filtered and the filtrate concentrated invacuum. The residue was partitioned between water and EtOAc and theorganic layer was then separated, dried and concentrated in vacuum. Theresidue was purified by flash chromatography (DCM: MeOH 100:0 to 95:5gradient) to give the title compound (400 mg). R_(f)=0.37 (95:5DCM:MeOH).

Step 63-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoicacid

To a solution of3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoicacid methyl ester (270 mg) in MeOH (10 ml) at room temperature was added4M NaOH (aq) (10 ml) and the reaction stirred overnight. The organic andaqueous layers were separated and the organic layer concentrated invacuum. The residue was triturated in toluene and diethyl ethersuccessively leaving the title compound (220 mg). R_(t)=0.96 min (methodE).

Synthesis of Building Block B17

Step 1

To a stirred solution of1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylicacid (500 mg) in DMF (5 ml) at room temperature was added DIPEA (1.1 ml)followed by HATU (1.1 g). After 45 min, intermediate I13 (0.34 g) wasadded and the reaction stirred overnight at rt. Saturated brine solutionwas added followed by EtOAc. The organic layer was separated, dried andconcentrated in vacuum and the residue purified by HPLC to give theproduct (557 mg). (R_(t) 1 50 min, method D)

Step 2

To a stirred solution of the product of step 1 (557 mg) in dioxane (5ml) was added lithium hydroxide (195 mg) dissolved in a sufficientamount of water. After overnight stirring, the reaction was acidifiedwith HCl(aq) (4M), then concentrated in vacuum. The residue was purifiedby HPLC to afford building block B17 (155 mg). (R_(t) 1.34 min, methodD).

Synthesis of I13 for Building Block B17

Step 1 Ethyl 2-bromo-4-methyl-3-oxopentanoate

To a suspension of sodium acetate (1.9 g) in glacial acetic acid (15 ml)was added 4-methyl-3-oxo-pentanoic acid ethyl ester (2 g) and thereaction mixture cooled to 10° C. Bromine (0.7 ml) was then addeddropwise. The resulting solution was allowed to warm to room temperatureand stirred for 1 h. The reaction was complete (by TLC) and wasconcentrated in vacuum affording 3.8 g crude ethyl product which wasused directly in the next synthetic step.

Step 2 Ethyl 2-amino-4-isopropylthiazole-5-carboxylate (I13)

A solution of thiourea (1.1 g) in ethanol (10 mL) was brought to reflux.Ethyl 2-bromo-4-methyl-3-oxopentanoate (3.0 g) was then added and thereaction mixture refluxed further for 1 h. The reaction was complete (byTLC) and was concentrated in vacuum. Flash chromatography (100%DCM→90:10 DCM:MeOH) afforded the product (1.1 g).

Synthesis of Building Block B18

Intermediate I14 was synthesized according to procedure D withsubsequent saponification.

Synthesis of Intermediate I16

2-chloro-6-methylnicotinic acid (9 g), of aq ammonia (44 ml), ofCu(II)SO₄ (0.9 g) and of sodium sulphide (0.32 g) were added to anautoclave and heated to 155° C. overnight. The crude product wassuspended in water to yield product 115 (3.6 g). The filtrate wasconcentrated and again suspended in water to yield a further 1.9 g ofproduct 115. HPLC: R_(t)=0.37 min (method D)

Step 2

To 50 ml of MeOH was added dropwise acetylchloride (3 ml) at rt. After15 min, intermediate I15 (2.3 g) was added and the mixture was stirredovernight at 50° C. After concentrating the solution, the resultingresidue was suspended in acetone and then filtered and dried at 50° C.in vacuum, to yield product 116 (4.1 g).

HPLC: R_(t)=0.91 min (method D)

Synthesis of Building Block B19

B19 was synthesized in analogy to B17. Synthesis of I13a for buildingblock B19 was analogous to that for I13.

Synthesis of Building Block B20

B20 was synthesized in analogy to B17. Synthesis of I13b for buildingblock B20 was analogous to that for I13.

S.2.3. Synthesis of Building Blocks with Formula C Synthesis of BuildingBlock C1

Building block A1, as its N,N-diisopropylethylamine salt (500 mg), wassuspended in dry DMF (7 ml) under inert atmosphere and TBTU (836 mg) wasadded, followed by N,N-diisopropylethylamine (0.53 ml). After stirringfor 1 h at room temperature, hexamethyldisilazane (0.44 ml) was addedand the mixture was stirred for 6 h. Further portions of TBTU (334 mg)and hexamethyldisilazane (0.22 ml) were added and the reaction wasstirred for further 18 h. The solvent was evaporated under reducedpressure and residue partitioned between saturated aqueous solution ofNaHCO₃ and EtOAc. The layers were separated and the aqueous phaseextracted with EtOAc. The combined organic extracts were washed withbrine, dried under Na₂SO₄, filtered and the solvent was evaporated underreduced pressure. The crude was purified by flash chromatography (20 gIsolute® silica gel cartridge; eluent: DCM/MeOH/NH₄OH 95/5/0.5)affording the title compound. (295 mg). HPLC (R_(t))=1.24 min (method M)

S.2.4. Synthesis of Building Blocks with Formula D Synthesis of BuildingBlock D1

Intermediate I17 was prepared starting from(R)-2-amino-3-tert-butoxycarbonylamino-propionic acid methyl esterhydrochloride (10.00 g) and 4-oxo-piperidine-1-carboxylic acid phenylester (12.07 g), following the procedures described for the synthesis ofI9. Product obtained 19.50 g (content 70%). HPLC (R_(t))=3.20 min(method Q)

Intermediate I18 was prepared starting from I17 (19.5 g, content 70%)and following the procedures described for the synthesis of I10. Productobtained 12.50 g (content 75%).

HPLC (R_(t))=1.96 min (method H)

Intermediate I19 was prepared starting from I18 12.50 g (content 75%)and following the procedures described for the synthesis of I11. Productobtained=2.90 g. HPLC (R_(t))=2.79 min (method H)

Intermediate I20 was prepared starting from I19 (2.70 g) and followingthe procedures described for the synthesis of I12. Product obtained=2.45g (content 85%) used in the next step without any further purification.HPLC (Rt)=3.00 min (method H)

To an ice-chilled solution of intermediate I20 (2.40 g, content 85%) inTHF (60 ml) and water (10 ml) was added lithium hydroxide monohydrate(0.68 g, 16.30 mmol). The temperature was allowed to warm to 25° C. andthe resulting solution stirred until complete disappearance of thestarting material (3 h). The organic solvent was evaporated underreduced pressure, the aqueous residue diluted with water 10 ml),acidified to pH 2.5 with 4N HCl. EtOAc (50 ml) was added, the phasesseparated, the organic layer washed with brine (20 ml), dried overNa₂SO₄ and evaporated to dryness. The residue was triturated with a 1/1n-hexane/Et₂O mixture, the solid dried at 40° C. under vacuum to affordI21 (1.90 g). HPLC (R_(t))=2.65 min (method H)

Intermediate I21 (1.80 g) was dissolved in dry DMF (15 ml), and theresulting solution stirred in a nitrogen atmosphere. HATU (2.46 g) andDIPEA (3.22 ml) were added sequentially and the whole stirred at roomtemperature for 30 min. 3-cyclopropyl-1-methyl-1H-pyrazole-5-amine (1.02g) was then added in one portion and the reaction mixture heated at 40°C. overnight. Extra HATU (2.27 g) and3-cyclopropyl-1-methyl-1H-pyrazole-5-amine (0.68 g) were then added, andthe heating maintained for 8 h. The reaction mixture was concentratedunder reduced pressure, the resulting residue diluted with water (40 ml)and EtOAc (50 ml). The layers were separated and the organic phasewashed with 1M HCl (3×20 ml), 10% aq. Na₂CO₃ (2×20 ml), water (1×20 ml)and brine (1×25 ml), dried over Na₂SO₄ and evaporated to dryness,affording a solid. The residue was triturated with diisopropyl ether,affording product I22 (1.70 g). HPLC (R_(t))=2.85 min (method H)

A suspension of 10% Pd/C (211 mg) in 80% aq. ethanol (5 ml) was added toa stirred solution of intermediate I22 (1.7 g, content 90%) in EtOH (30ml). The whole was then stirred under a positive pressure of hydrogen.After 4 h extra catalyst (100 mg) was added and the conditionsmaintained overnight. The reaction mixture was then filtered overCelite®, the cake carefully washed with EtOH (3×10 ml) and the filtrateevaporated to dryness under reduced pressure. The residue was dissolvedin an 8/2 EtOAc/MeOH mixture (30 ml) and treated with HCl (6 ml of a 4Nsolution in 1,4 dioxane) to form the corresponding hydrochloride salt.The solvent was evaporated to dryness and the residue triturated withMTBE, the solid filtrated and dried at 40° C. under vacuum to afford thebuilding block D1 (1.20 g). HPLC (R_(t))=1.60 min (method H)

Synthesis of Building Block D2

Example 35 (1.0 g) was dissolved in MeOH (20 ml), and Pd/C was added andthe mixture was hydrogenated at 50° C. and 50 psi for 12 h. After thisperiod, further Pd/C was added and the mixture was again hydrogenated at50° C. and 50 psi for 7 h. The solution was then filtered andconcentrated in vacuum to give 0.62 g of building block D2 which wasused without further purification. HPLC: 0.98 min (method D)

Synthesis of Building Block D3

Building block D3 was prepared in analogy to building block D2 startingfrom example 135.

S.2.5 Synthesis of Intermediate I12.2 (Building Block for Procedure E)

see synthesis of building block A6, step 4.

S.2.6. Synthesis of Building Blocks with Formula F Synthesis of BuildingBlock F1

2-Chloro-6-methyl-isonicotinamide (1.23 g) and N,N-dimethylformamidedimethyl acetal (1.05 ml) were dissolved in dry DMF (4 ml) under inertatmosphere and the resulting solution was heated to 90° C. and stirredfor 1 h. The reaction mixture was cooled to room temperature and asolution of hydrazine acetate (3.32 g) in acetic acid (8 ml) wasdropwise added. The mixture was heated to 90° C. and stirred for 1 h.The solvent was removed under reduced pressure and the residuepartitioned between saturated aqueous solution of NaHCO₃ and EtOAc. Theorganic phase was separated, washed with brine, dried under Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Thecrude was purified by flash column chromatography (10 g Isolute® silicagel cartridge; gradient elution: hexane/EtOAc from 1/1 to 3/7) affording2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (0.92 g). GC(R_(t))=13.21 min (method=3A)

Step 2

2-Chloro-6-methyl-4-(1H-[1,2,4]triazol-3-yl)-pyridine (120 mg) and3,4-dihydro-2H-pyran (84 μL) were suspended in dry DCM (3.5 mL) underinert atmosphere and pyridinium p-toluenesulfonate (15.5 mg) was added.The reaction mixture was stirred at room temperature for 18 h. Thesolution was diluted with DCM, washed with water and brine, dried underNa₂SO₄, filtered and the solvent was evaporated under reduced pressure.The crude was purified by flash column chromatography (10 g Isolute®silica gel cartridge; eluent: hexane/EtOAc 3/7) affording product (155mg). HPLC (R_(t))=1.51 min (method M)

Step 3

2-Chloro-6-methyl-4-[1-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine(33.0 mg, 0.12 mmol) and building block C1 were dissolved in dry dioxane(1.2 mL) under inert atmosphere and palladium(II)acetate (2.12 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.9 mg) and caesiumcarbonate (81.0 mg) were added subsequently. The mixture was heated to100° C. and stirred for 18 h. After cooling to room temperature thereaction mixture was diluted with DCM, washed with water and brine,dried under Na₂SO₄, filtered and the solvent was evaporated underreduced pressure. The crude was purified by flash column chromatography(10 g Isolute® silica gel cartridge; gradient elution: DCM/MeOH from97/3 to 95/5) affording building block F1 (70 mg). HPLC (R_(t))=1.75 min(method M)

Syntheses of Building Blocks F2 and F3

Building blocks F2 and F3 were prepared in analogy to building block F1

The chloropyridines were prepared as follows:

2-Chloro-4-[4-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine

2-Chloro-4-[4-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridinewas prepared in analogy to2-Chloro-6-methyl-4-[1-(tetrahydro-pyran-2-yl)-1H-[1,2,4]triazol-3-yl]-pyridine.HPLC (R_(t))=1.68 min (method M)

2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine

4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazole (0.73 g) and2-chloropyridine-4-boronic acid (0.20 g) were dissolved in dry DMF (2mL) under inert atmosphere and1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)(102 mg) wasadded followed by caesium carbonate (0.84 g). The mixture was heated to80° C. and stirred for 2 h. After cooling to room temperature thereaction mixture was diluted with DCM and the inorganic salts filteredoff. The filtrate was washed with water and brine, dried under Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Thecrude was purified by flash chromatography (20 g Isolute® silica gelcartridge; gradient elution: hexane/EtOAc from 10/0 to 8.5/1.5)affording the title compound (144 mg). HPLC (R_(t))=1.39 min (method M)

S.3 Synthesis of Reaction Partners for Procedures A-F S.3.1. Synthesisof Primary or Secondary Amines for Procedures A and B Synthesis of (I25)for Example 7

To a stirred mixture of 5-nitroisophthalic acid (20.0 g) in DCM wasadded oxalyl chloride (36 ml, 2M in DCM), followed by DMF (0.5 ml). Themixture was stirred for 2 h at room temperature, before volatiles wereremoved in vacuum. The residue was suspended in dry toluene andconcentrated again to yield crude I23 (10 g), which was used withoutfurther purification in the next step.

Step 2

I23 (10 g) was dissolved in THF (20 ml) and added dropwise to a solutionof methylamine (40 ml, 2M in THF) in THF (80 ml) under stirring at −20°C. After 20 min, the mixture was filtered, and the filtrate concentratedin vacuum. The residue was triturated with diethylether to form a solidthat was filtered off and dried to yield intermediate I24 (3.53 g)

Step 3

A solution of intermediate I24 (0.52 g) in MeOH (30 ml) was treated withhydrogen (50 psi) in the presence of Raney-Nickel (90 mg) at roomtemperature for 14 h. The mixture was then filtered and concentrated invacuum to afford I25. The compound was used without further purificationin the next step.

HPLC (R_(t))=0.33 min (method D)

Synthesis of N-(8-amino-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)acetamidefor Example 10

This intermediate was synthesized according to WO2006040279.

Synthesis of N-(4-Amino-cyclohexyl)-benzenesulfonamide for Example 29

This intermediate was synthesized analog to WO2001096295.

Synthesis of 3-(4-Amino-2-methyl-phenyl)-[1,3]oxazinan-2-one for Example30

This intermediate was synthesized analog to WO2005111029.

Synthesis of 5-Amino-2,3-dihydro-indole-1-carboxylic acid methylamidefor Example 37

This intermediate was synthesized analog to WO2008113760.

Synthesis of 1-(3-Amino-benzyl)-3-cyclohexyl-urea for Example 39

Step 1: 1-Cyclohexyl-3-(3-nitro-benzyl)-urea

3-Nitro-benzyl-amine (5 g) was suspended in THF (130 ml) and cyclohexylisocyanate (7 ml) was added dropwise at 25° C. After stirring for 2 hthe resulting precipitate was filtered off, washed with diethyl etherand treated with 5% aqueous NH₄OH. After filtering and drying the titlecompound was isolated (4.5 g, FP 168-169° C.)

Step 2: 1-(3-Amino-benzyl)-3-cyclohexyl-urea

1-Cyclohexyl-3-(3-nitro-benzyl)-urea (4 g) was suspended in ethanol (70ml) and Raney nickel (2 g) was added. Under stirring aqueous hydrazinesolution (2.5 ml, 80%) was added. DMF was added (50 ml) and the reactionmixture was stirred for additional 2 h and filtered. The solution wasevaporated i.v. affording the title compound (3 g, R_(f)=0.43DCM/ethanol 19:1).

Synthesis of trans-1-(4-Amino-cyclohexyl)-3-phenyl-urea for Example 44

This intermediate was synthesized analog to WO2005095339.

Synthesis of 1-Methanesulfonyl-pyrrolidin-3-ylamine for Example 53

This intermediate was synthesized analog to WO2006118256.

Synthesis of 3-Pyridin-4-ylmethyl-phenylamine for Example 66

This intermediate was synthesized analog to WO2004009546.

Synthesis of 1-(5-Chloro-1H-benzoimidazol-2-yl)-2-methoxy-ethylamine forExample 67

This intermediate was synthesized analog to WO2004056784.

Synthesis of C-(6-Chloro-2-methyl-pyridin-3-yl)-methylamine for Example70

Step 1 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile

A solution of (E)-3-amino-but-2-enenitrile (100 g) and propynoic acidmethyl ester in DMF (200 ml) was stirred at 25° C. for 2 h and refluxedfor additional 1 h. Dowtherm (100 ml) was added and the temperature wasrised to 230° C. DMF and MeOH were distilled off. The reaction mixturewas cooled down, EtOAc (200 ml) was added and the resulting crystalswere filtered off and washed with EtOAc and ether affording the titlecompound (44.8 g, FP>250° C.).

Step 2 6-Chloro-2-methyl-nicotinonitrile

A mixture of 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (44 g)and POCl3 (250 ml) was refluxed for 3 h. The reaction mixture was drieddown in vacuum and ice followed by conc. aqueous ammonia (300 ml) wasadded. The aqueous layer was extracted with EtOAc. The organic layer wasseparated, dried and concentrated in vacuum affording the title compound(23.5 g, BP (18 mbar) 119-120° C.).

Step 3 C-(6-Chloro-2-methyl-pyridin-3-yl)-methylamine

To a solution of 6-Chloro-2-methyl-nicotinonitrile (6 g) in THF (120 ml)at 25° C. was added NaBH₄ (3 g) followed by the dropwise addition of BF₃etherate (6 ml). The reaction mixture was stirred for 3 h. MeOH (100 ml)and 2N HCl (100 ml) was added and refluxed for 1 h. The organic solventwas removed in vacuum and conc. NaOH (40 ml) was added followed byextraction with diethyl ether. The organic layer was separated, driedand concentrated in vacuum followed by filtration over silica gel(EtOAc/MeOH 80:20). The title compound was crystallized from MeOH/HCl(5.5 g)

Synthesis ofN-(3-aminophenyl)-N-(2-(azetidin-1-yl)-2-oxoethyl)methanesulfonamide forExample 75

This intermediate was synthesized analog according to WO2006114371.

Synthesis of N-(3-aminophenyl)-methylsulfonamido)-N,N-dimethylacetamidefor Example 76

This intermediate was synthesized analog to WO2006114371.

Synthesis ofN-(3-aminophenyl)-cyclopropane-sulfonamido)-N,N-dimethylacetamide forExample 78

This intermediate was synthesized analog according to WO2006114371.

Synthesis of2-[(3-Amino-phenyl)-ethanesulfonylamino]-N,N-dimethyl-acetamide forExample 79

This intermediate was synthesized analog to WO2006114371.

Synthesis of ethyl 5-amino-3-methylbenzoate for example 88

2 g acid was dissolved in 22 mL ethanolic HCl and stirred at 60° C. for2 days. The mixture was then concentrated and used without furtherpurification.

Synthesis of ethyl 3-methylaminobenzoate for Example 92

2 g acid was dissolved in 22 mL ethanolic HCl and stirred at 60° C. for2 days. The mixture was then concentrated and used without furtherpurification.

Synthesis of 4-(3,5-Dimethyl-pyrazol-1-yl)-pyridin-2-ylamine for Example102

A 10 ml microwave reaction vessel was charged with 4-Chloro-pyridinamine(0.5 g) and 3,5-dimethylpyrazole (1.12 g); hydrochloric acid (37%, 0.5ml) and dioxane were then added. The reaction mixture was irradiated ina Microwave oven with the following parameters: potency: 150 W;temperature: 120° C.; time: 180 min.

The reaction mixture was cooled at room temperature and treated withdiethyl ether (2 ml) and ethanol (1 ml) and sonicated during 30 min. Atend of treatment the mixture was cooled during 14 h at 4° C. A solid wasfiltered off and washed with diethyl ether and n-hexane to furnish theproduct as the hydrochloride salt (450 mg).

Synthesis of 5-amino-tetramethylisophthalamide (I29) for Example 105

To a stirred solution of mono methyl 5-nitroisophthalate (1.0 g) andDIPEA (1.43 ml) in DCM (30 ml) and DMF (3 ml) was added HATU (1.69 g) atrt. After 10 min, dimethylamine (4.4 ml, 2M solution in THF) was addedand stirring was continued for 12 h. Water and sodium bicarbonate wereadded to the reaction mixture and extracted with DCM. The organic layerwas separated and concentrated in vacuum. The reside was furtherpurified by normal phase MPLC (cyclohexane: EtOAc=80:20 to 30:70) toafford intermediate I26 (0.91 g)

HPLC (R_(t))=1.29 min (method D)

Step 2

A mixture of I26(2.5 g), MeOH (20 ml) and LiOH(aq) (8 wt. %, 5.9 ml) wasstirred at 50° C. for 1 h. Volatiles were then removed in vacuum and theresidue was acidified by treatment with 2 M HCl (aq). The mixture waslyophilized, the remaining solid suspended in water and warmed to 50° C.The resulting suspension was filtered, the solid was washed with waterand petrolether and dried in vacuum at 50° C. to yield 127 (1.56 g) thatwas used without further purification.

HPLC (R_(t))=0.27 min (method E)

Step 3

HATU (707 mg) was added in two portions to a mixture of 127 (400 mg),DCM (5 ml), DMF (2 ml), diisopropylamine (0.68 ml), and HOBt (227 mg)under stirring at rt. Dimethylamine (2.1 ml, 2M in THF) was added andstirring continued for 48 h. Water and sodium bicarbonate were thenadded and the resulting mixture was extracted with DCM. The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuum. Theresidue was further purified by reversed phase HPLC the productcontaining fractions were combined volatiles removed in vacuum and theremaining aqueous mixture extracted with DCM. The organic layer wasconcentrated to afford I28 (71 mg).

Step 4

A solution of intermediate I28 (71 mg) in MeOH (10 ml) was treated withhydrogen in the presence of Raney-Nickel (10 mg) at rt. The mixture wasthen filtered and concentrated in vacuum to afford the title compoundI29 (40 mg). The compound was used without further purification in thenext step.

HPLC (R_(t))=0.70 min (method D)

The reaction partners for example 107 and 106 were synthesizedanalogously as for example 105.

Intermediate for the synthesis of HPLC example Structure method R_(t)[min] 107

D 1.26 106

D 1.26

Synthesis of methyl 3-amino-5-(dimethylcarbamoyl)benzoate for Example108

A solution of intermediate I26 (0.91 g) in MeOH (40 ml) was treated withhydrogen in the presence of Raney-Nickel (90 mg) at rt. The mixture wasthen filtered and concentrated in vacuum to afford the title compound(810 mg). The compound was used without further purification in the nextstep.

HPLC (R_(t))=0.98 min (method D)

Synthesis of methyl 3-amino-5-methoxy benzoate for the Synthesis ofExample 111

To a stirred suspension of 3-amino-5-methoxy benzoic acid (500 mg) in amixture of DCM (4.0 ml) and MeOH (2.0 ml) at 0° C. was added a solutionof trimethylsilyldiazomethan in hexane (3.39 ml, 2M) dropwise. After 15min, the reaction was concentrated in vacuum. The remaining crudeproduct was purified by reversed phase HPLC to yield thetrifluoroacetate salt of title compound (280 mg).

HPLC (R_(t))=1.02 min (method D)

Synthesis of ethyl 3-amino-5-chloro benzoate for the Synthesis ofExample 112

5-tert-butylisophthalic acid (1.3 g) was dissolved in MeOH (20 ml). Theresulting solution was cooled to 0° C. and thionlychloride (0.45 ml) wasadded dropwise under stirring. After complete addition, the mixture wasallowed to warm to room temperature and was stirred for additional 7 h.The mixture was then poured on an ice cold sodium bicarbonate solutionand extracted repeatedly with EtOAc. The aqueous phase was acidifiedwith HCl and again extracted with EtOAc. The combined organic layerswere washed with brine and concentrated in vacuum. The residue wasworked up by flash column chromatography on silica gel (DCM:MeOH=20:1)to yield methyl 5-tert-butylisophthalate (1.3 g).

Step 2

Under an atmosphere of argon, 5-tert-butylisophthalate (0.5 g) wasdissolved in tert.-butanol (20 ml). To the resulting solution,triethylamine (0.35 ml) and diphenyl phosphoreazidate (0.56 ml) wereadded subsequently. The mixture was then heated to reflux for 12 h,cooled to room temperature and concentrated in vacuum. The residue wastaken up in EtOAc, and subsequently washed with dilute aqueous citricacid, saturated sodium bicarbonate solution and brine. The organic layerwas concentrated in vacuum and the residue was worked up by flashchromatography (petrol ether:EtOAc=3:1) to yield methyl3-(tert.-butoxycarbonylamino)-5-tert-butylbenzoate (0.61 g).

Step 3

Methyl 3-(tert.-butoxycarbonylamino)-5-tert-butylbenzoate (0.42 g) wasdissolved in DCM (5 ml). To the resulting solution, TFA (1 ml) wasadded, the mixture was stirred for 30 min at room temperature and thenconcentrated in vacuum. The residue was dissolved in DCM and extractedwith aqueous sodium bicarbonate solution. The organic layer wasseparated, dried over sodium sulphate and concentrated in vacuum toyield ethyl 3-amino-5-tert-butylbenzoate (0.28 g), which was used forthe synthesis of example 112 without further purification.

Synthesis of methyl 3-amino-5-chloro benzoate for the Synthesis ofExample 113

A solution of methyl 3-chloro-5-nitrobenzoate (300 mg) in THF (50 ml)was treated with hydrogen (3 bar) in the presence of Raney-Nickel (10mg) at rt. The mixture was then filtered and concentrated in vacuum toafford the title compound (204 mg). The compound was used withoutfurther purification in the next step.

HPLC (R_(t))=1.36 min (method D)

Synthesis of 3-Methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine forExample 114

Step 1

3-Chlorocarbonyl-5-nitro-benzoic acid ethyl ester

To a solution of 5-nitroisophtalic acid monoethyl ester (80 g) in DCM(700 ml) at 25° C. was added 2M oxalyl chloride solution in DCM (63 ml),and DMF (5 ml). The reaction was stirred for 2 h and then concentratedin vacuum. The residue was triturated with toluene and againconcentrated in vacuum leaving the title compound (60 g). R_(t)=1.40 minfor derivatised methylester (method D).

Step 2 N-Methyl-5-nitro-isophthalamic acid ethyl ester

To a 2M solution of methylamine in THF (256 ml) at −20° C. was added apre-cooled solution of 3-chlorocarbonyl-5-nitro-benzoic acid ethyl ester(60 g) in THF (500 ml) dropwise. This was stirred for 20 min and thenfiltered. The filtrate was concentrated in vacuum and the solidrecrystallised from diethyl ether to give the title compound (22.5 g) asa solid. An oxalyl chloride solution in DCM (63 ml, 2M), was added withDMF (5 ml). The reaction was stirred for 2 h and then concentrated invacuum. The residue was triturated with toluene and again concentratedin vacuum leaving the title compound (60 g). R_(t)=1.53 min (method D).

Step 3 3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethyl ester

To a 2M solution of N-methyl-5-nitro-isophthalamic acid ethyl ester (10g) in dichloroethane (200 ml) at −20° C. was added pre-cooled triflicanhydride (10 ml) dropwise. This was stirred for 30 min and then sodiumazide (4.6 g) was added. This was allowed to warm to room temperatureand stirred overnight. The reaction was neutralised with 5% NaHCO₃ (aq)solution and the organic and aqueous layers were separated and theorganic layer dried and concentrated in vacuum. Flash chromatography(100:0 to 50:50 gradient cyclohexane:EtOAc) afforded the title compound(6.5 g). R_(t)=1.52 min (method D).

Step 4 3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid ethyl ester

A solution of 3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethylester (6.5 g) in EtOAc:ethanol (1:1, 320 ml) was hydrogenated at 20° C.and 50 psi with 10% Pd/C (750 mg). After reaction completion, themixture was filtered and the filtrate concentrated in vacuum to give thetitle compound (4.2 g). R_(t)=1.21 min (method D).

Step 5 [3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-methanol

To a solution of 3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acidethyl ester (250 mg) in THF (5 ml) at 0° C. was added pre-cooled 1MLiAlH₄ solution in THF (2 ml) dropwise. This was stirred for 3 h. Thereaction mixture was poured onto ice-water and extracted into EtOAc. Theorganic layer was separated, dried and concentrated in vacuum. Flashchromatography (100:0 to 95:5 gradient DCM:MeOH) afforded the titlecompound (70 mg).

R_(f)=0.19 (DCM:MeOH 95:5).

Step 6 3-Methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine

A solution of [3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-methanol(450 mg) in MeOH (20 ml) with a few drops of conc. HCl (aq) washydrogenated on a H-cube apparatus at 30° C., and 10 bar with a flowrate of 1 mL/min using a Pd/C cartridge. After reaction completion, themixture was concentrated in vacuum and the residue basified with adilute K₂CO₃(aq). This was extracted with EtOAc and the organic layerwas separated, dried and concentrated in vacuum. The residue waspurified by flash chromatography (98:2 DCM:MeOH) to give the titlecompound (320 mg).

R_(f)=0.46 (95:5 DCM:MeOH)

S3.2 Synthesis of aromatic-chlorides or -bromides for Procedure CSynthesis of 2-Chloro-4-(3,5-dimethyl-isoxazol-4-yl)-pyridine forExample 187

The title compound was prepared from 4-bromo-3,5-dimethylisoxazolegenerally according to the synthetic procedure described for2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine. HPLC(R_(t))=0.81 min (method N)

Synthesis of2-Chloro-6-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridine forExample 188

To a suspension of 2-chloro-6-methyl-isonicotinamide (0.50 g, 2.93 mmol)in dry DCM (10 ml), dry pyridine (0.26 ml) was added and the mixture wascooled to 0° C. under inert atmosphere. Trifluoroacetic anhydride (0.45ml) was added dropwise under stirring, the cooling bath was removed andthe reaction mixture was stirred for 4 h. After this period otherportions of pyridine (0.074 ml) and trifluoroacetic anhydride (0.12 ml)were added and the mixture stirred at room temperature for further 3 h.

The reaction was quenched with aqueous solution of NaHCO₃, the phaseswere separated and the aqueous layer extracted with DCM. The combinedorganic extracts were washed with brine, dried under Na₂SO₄, filteredand the solvent was evaporated under reduced pressure. The crude productwas obtained (0.378 g) and used in next step without furtherpurification. HPLC (R_(t))=1.65 min (method M)

2-Chloro-6-methyl-isonicotinonitrile (378 mg) was dissolved in ethanol(4 ml) and hydroxylamine hydrochloride (379 mg) was added followed by asolution of sodium carbonate (577 mg) in water (8 ml). The reactionmixture is heated to 75° C. and stirred for 18 h. Ethanol was evaporatedunder reduced pressure and the aqueous residue extracted with EtOAc. Thecombined extracts were washed with water and brine, dried under Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Thecrude product was obtained (401 mg) and used in next step withoutfurther purification. HPLC (R_(t))=0.67 min (method M)

2-Chloro-N-hydroxy-6-methyl-isonicotinamidine (120 mg) was suspended intrimethylorthoacetate (3 ml) under inert atmosphere and acetic acid (0.3ml) was added. The mixture was heated to 100° C. and stirred for 2 h.After cooling to room temperature the solvent was evaporated underreduced pressure and the residue partitioned between EtOAc and aqueoussolution of NaHCO₃. The organic layer was separated, washed with waterand brine, dried under Na₂SO₄, filtered and the solvent was evaporatedunder reduced pressure. The crude was purified by flash columnchromatography (10 g Isolute® silica gel cartridge; gradient elution:hexane/EtOAc from 10/0 to 9/1) affording the title compound (107 mg).

HPLC (R_(t))=3.17 min (method L).

Synthesis of methyl 2,6 dibromo-isonicotinate for the Synthesis ofExample 194

In a three necked round bottom flask equipped with a mechanic stirrerand gas outlet solid cirtrazinic acid (15 g) and phosphorous oxybromide(45 g) were thoroughly mixed and heated to 140° C. for 12 to 14 h. Theresulting mixture was cooled to 0° C. before MeOH (100 ml) was addedcarefully under vigorous stirring. The resulting mixture was then pouredinto a cooled (0° C.) aqueous sodium carbonate solution (1M, 500 ml),before Chloroform (500 ml) was added. The biphasic mixture was filteredthrough a paper filter, before the organic layer was separated. Afterfiltering through charcoal, the solution was concentrated in vacuum. Theresidue was purified by MPLC (DCM:MeOH=100:3 to 100:6) to yield methyl2,6 dibromo-isonicotinate (13.7 g).

HPLC (R_(t))=1.62 (method D)

Synthesis of methyl 2-bromo-6-methoxyisonicotinate for Example 195

A solution of sodium methoxide (375 mg) and methyl 2,6dibromo-isonicotinate (1.0 g) in MeOH (20 ml) was heated in a microwaveoven at 130° C. for 30 min. Then additional sodium methoxide (281 mg)was added and heating continued for additional 15 min at 130° C.Concentrated sulfuric acid (1.86 ml) was then added to the reactionmixture and the resulting suspension was heated for 4 h at 80-85° C.

After cooling to room temperature, the mixture was poured in an ice coldaqueous sodium carbonate solution (100 mL) and extracted with DCM (100ml). The organic layer was separated, dried over Na₂SO₄ and concentratedin vacuum. The residue was purified by MPLC (DCM:MeOH=100:3 to 100:5) toyield 710 mg of a 70:30 mixture of desired product (497 mg) and thecorresponding trimethyl cirtrazinic acid (213 mg). The mixture was usedfor subsequent transformations without further purification.

HPLC (R_(t))=1.66 min (method D)

Synthesis of 2-Chloro-6-methyl-4-(1-methyl-1H-tetrazol-5-yl)-pyridinefor Example 191

Step 1 2-Chloro-6,N,N-trimethyl-isonicotinamide

To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min,dimethylamine (0.75 g) was added dropwise. This was stirred overnight.The reaction was added to water and extracted with EtOAc. The organiclayer was separated, dried and concentrated in vacuum.Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) affordedthe title compound (320 mg). R_(f)=0.56 (1:1 cyclohexane:EtOAc)

Step 2 2-Chloro-6-methyl-4-(1-methyl-1H-tetrazol-5-yl)-pyridine

To a solution of 2-Chloro-6,N,N-trimethyl-isonicotinamide (2.3 g) inacetonitrile (30 ml) at −15° C. was added DCM (20 ml) pre-cooled triflicanhydride (3 mL) dropwise. This was stirred for 10 min at −10° C. andthen sodium azide (4.6 g) was added. This was allowed to warm to roomtemperature and after 2 h, the reaction was neutralised with a cold 5%NaHCO₃(aq) solution and extracted with EtOAc. The organic layer wasseparated, dried and concentrated in vacuum. Flash chromatography (100:0to 40:60 gradient cyclohexane:EtOAc) afforded the title compound (260mg). R_(t)=1.21 min (method D).

S.4. Synthesis of Examples According to Procedure A to G S.4.1.Synthesis of Examples According to Procedure A Examples 1-131 AmideFormation Method A

To a stirred solution of building block A (1 eq) in DMF, NMP, DCM orchloroform at room temperature is added DIPEA or TEA (2-8 eq), HATU orTBTU (1-4 eq) and HOBt (0-2 eq). After 20-45 min, amine reaction partner(1.2-2 eq) is added and the mixture stirred for an additional 40-120min. Water and TFA is then added and the mixture is separated viareversed phase HPLC to provide the desired amides. The reaction mixturecan be filtered over basic ALOX or extracted with DCM after addition ofaqueous NaHCO₃ solution followed by concentrating the organic fractionsin vacuum before the HPLC purification.

Synthesis of Example 1

Building block A1 (60 mg) was dissolved in NMP (0.5 ml) and DIPEA (0.15ml). HATU (120 mg) was added and the solution was stirred for 45 min atrt. 3-(1-methyl-1H-tetrazol-5-yl)aniline (34 mg) was added and themixture was stirred for a further 1 h. A few drops of water and TFA wereadded and the mixture was separated via reversed phase HPLC. The desiredfractions were collected, combined and lyophilised to yield example 1(18 mg) as the TFA salt. HPLC: 1.3 min (method D)

Amide Formation Method B

To a stirred solution of building block A (1 eq) in DCM at roomtemperature is added oxalylchloride (2-5 eq, neat or 2M solution in DCM)and the mixture stirred for 0.5-2 h and then concentrated in vacuum.Pyridine, DMAP (0-0.1 eq) and amine reaction partner (2-3 eq) is addedand the mixture stirred for 1-2 h, then concentrated, dissolved in ACN,water and TFA and separated via reversed phase HPLC to give the desiredamides.

Synthesis of Example 2

Building block A1 (80 mg) was dissolved in DCM (2 ml), and a solution ofoxalylchloride in DCM (0.2 ml, 2M) was added and the mixture was stirredat 25° C. for 2 h and then concentrated in vacuum. Pyridine (1 ml) and3-amino-N-methyl-5-(trifluoromethyl)benzamide hydrochloride (88 mg) isadded and the mixture was further stirred for 2 h, then concentrated,dissolved in acetonitrile, water and TFA and separated via reversedphase HPLC to give of example 2 (45 mg) as the TFA salt. HPLC: 1.37 min(method D)

Synthesis of Example 3

Building block A1 (80 mg) was dissolved in DCM (2 ml), oxalylchloride(0.07 ml) was added and the mixture was stirred at room temperature for0.75 h and then concentrated in vacuum. Pyridine (1 ml),4-dimethylaminopyridine (2 mg) and5-Amino-1,3,4-thiadiazole-2-carboxylic acid ethyl ester (60 mg) wereadded and the mixture was further stirred for 1 h, then concentrated,dissolved in acetonitrile and separated via reversed phase HPLC to giveexample 3 (17 mg). HPLC: 1.34 min (method D)

The following examples 4-115 were synthesized in analogy to example 1-3from building blocks A1 to A4.

Amide R_(t) [min] formation Building # R² R¹ R³, R⁴ * (method) Methodblock 4

H, H R 1.26 (D) A A1 5

H, H R 1.36 (D) A A1 6

H, H R 1.35 (D) A A3 7

H, H R 1.21 (D) A A1 8

H, H R 1.29 (D) A A1 9

H, H R 1.35 (D) A A1 10

H, H R 1.34 (D) A A1 11

H, H R 1.30 (D) A A1 12

H, H S 1.20 (C) A A1 13

H, H R 1.39 (D) A A1 14

H, H R 1.36 (D) A A1 15

H, H R 1.39 (D) A A1 16

H, H R 1.26 (D) B A1 17

H, H R 1.55 (B) A A1 18

H, H R 1.61 (B) A A1 19

H, H R 1.46 (B) A A1 20

H, H R 1.74 (B) A A1 21

H, H R 1.61 (B) A A1 22

H, H R 1.80 (B) A A1 23

H, H S 1.51 (B) A A1 24

H, H R 1.53 (B) A A1 25

H, H R 1.25 A A3 26

H, H R 1.59 (B) A A1 27

H, H R 1.42 (B) A A1 28

H, H R 1.62 (B) A A1 29

H, H R 1.58 (B) A A1 30

H, H R 1.36 (B) A A1 31

H, H R 1.50 (B) A A1 32

H, H R 1.43 (B) A A1 33

H, H R 1.54 (B) A A1 34

H, H R 1.58 (B) A A1 35

H, H S 1.90 (B) A A2 36

H, H R 1.30 (B) A A1 37

H, H R 1.52 (B) A A1 38

H, H S 1.71 (B) A A1 39

H, H R 1.72 (B) A A1 40

H, H S 1.49 (B) A A2 41

H, H R 1.43 (B) A A1 42

H, H S 1.64 (B) A A1 43

H, H R 1.72 (B) A A1 44

H, H R 1.59 (B) A A1 45

H, H S 1.50 (B) A A2 46

H, H S 1.63 (B) A A2 47

H, H S 1.68 (B) A A2 48

H, H S 1.66 (B) A A2 49

H, H S 1.68 (B) A A2 50

H, H S 1.59 (B) A A2 51

H, H S 1.63 (B) A A2 52

H, H S 1.65 (B) A A2 53

H, H S 1.51 (B) A A2 54

H, H R 1.75 (B) A A2 55

H, H S 1.74 (B) A A2 56

H, H S 1.78 (B) A A2 57

H, H S 1.74 (B) A A2 58

H, H S 1.72 (B) A A2 59

H, H R 1.72 (B) A A2 60

H, H S 1.39 (B) A A2 61

H, H S 1.78 (B) A A2 62

H, H S 1.72 (B) A A2 63

H, H R 1.64 (B) A A2 64

H, H R 1.40 (B) A A2 65

H, H R 1.40 (B) A A2 66

H, H S 1.42 (B) A A2 67

H, H S 1.56; 1.64 (B) A A2 68

H, H R 1.61 (B) A A2 69

H, H S 1.44 (B) A A2 70

H, H S 1.62 (B) A A2 71

H, H S 1.72 (B) A A2 72

H, H S 1.68 (B) A A2 73

H, H S 1.70 (B) A A2 74

H, H R 1.68 (B) A A2 75

R 1.31 (E) A A4 76

R 1.31 (E) A A4 77

R 1.31 (E) A A4 78

R 1.33 (E) A A4 79

R 1.34 (E) A A4 80

R 1.38 (E) A A4 81

R 1.22 (E) A A4 82

R 1.24; 1.29 (E) A A4 83

R 1.45 (E) A A4 84

R 1.23 (E) A A4 85

R 1.33 (E) A A4 86

R 1.37 (E) A A4 87

H, H R 1.35 (D) A A1 88

H, H R 1.48 (D) A A1 89

H, H R 1.37 (D) A A1 90

H, H R 1.40 (D) A A1 91

H, H R 1.67 (B) A A1 92

H, H R 1.39 (D) A A1 93

H, H R 1.26 (D) A A1 94

H, H R 1.87 (A) A A1 95

H, H R 1.91 (A) A A1 96

H, H R 1.66 (B) A A2 97

H, H S 1.37 (B) A A2 98

H, H R 1.36 (D) B A2 99

H, H R 1.31 (D) B A1 100

H, H R 2.07 (A) A A1 101

H, H R 9.22 (O) A A1 102

H, H R 9.75 (O) A A1 103

H, H R 1.26 (D) B A1 104

H, H R 1.35 (D) A A1 105

H, H R 1.23 (D) B A1 106

H, H R 1.23 (D) A A1 107

H, H R 1.20 (D) A A1 108

H, H R 1.21 (D) B A1 109

H, H R 1.33 (D) A A1 110

H, H R 1.47 (D) B A1 111

H, H R 1.40 (D) A A1 112

H, H R 1.53 (D) A A1 113

H, H R 1.48 (D) A A1 114

H, H R 1.26 (E) A A1 115

H, H R 1.26 (D) A A3

Synthesis of Examples from Building Blocks A5-A8 Example 116

To an ice-chilled stirred solution of building block A5 (0.11 g),3-amino-benzonitrile (0.08 g), DIPEA (0.26 ml) and DMAP (0.01 g) in dryDMF (1 ml), was added tetramethyl fluoroformamidiniumhexafluorophosphate (0.1 mg). After 5 min the cooling bath was removedand the reaction mixture stirred at room temperature until completedisappearance of the starting acid.

The solvent and the volatiles were removed under reduced pressure, thethick oily residue was purified by preparative LC-MS, affording example116 (as TFA salt) (0.02 mg). HPLC (Rt)=8.38 min (method O)

The following examples are synthesized in analogy to the Preparation ofexample 116:

R_(t) [min] Building Example R¹ (method) block 117

8.27 (P) A5 118

6.90 (P) A5 119

8.38 (O) A5

Example 120

Building block A7 (0.07 g) was dissolved in dry DMF (2 ml); HATU (0.09g) and DIPEA (0.15 mL) were added in sequence and the whole stirred atroom temperature for 15 min. Then 3-pyridin-4-yl-phenylamine was added(0.04 g) and the resulting yellow solution stirred at 40° C. untilcomplete disappearance of the starting acid. The solvent and thevolatiles were removed under reduced pressure; the oily residue waspurified by preparative LC-MS, affording the title compound (as TFAsalt) (62 mg). HPLC (R_(t))=10.02 min, Method=F

The following examples are synthesized in analogy to the preparation ofexample 120

R_(t) [min] Building # R¹ * (method) block 121

R 7.33 (P) A7 122

R 6.90 (P) A7 123

R 7.08 (P) A7 124

S 3.05 (G) A8 125

S 2.88 (G) A8 126

S 2.43 (G) A8 127

S 8.27 (F) A8 128

S 2.72 (G) A8 129

S 2.49 (G) A8 130

R 2.67 (G) A6 131

R 2.49 (G) A6

S.4.2. Synthesis of Examples According to Procedure B Examples 132-191Synthesis of Example 132

To a stirred solution of Building block B1 (120 mg) in DMF (2 ml) atroom temperature, was added DIPEA (0.2 ml), HATU (175 mg). After 20 min,pyrrolidine (49 mg) was added and the mixture stirred for a further 1.5h. A few drops of water and TFA were added and the mixture was separatedvia reversed phase HPLC. The desired fractions were collected, combinedand lyophilised to yield example 132 (30 mg) as the TFA salt. HPLC:R_(t)=1.29 min (method D)

The following examples have been synthesized from building block B1 toB18 in analogy to example 132.

R_(t) [min] # R¹ X * (method) Building block 133

Cl R 1.34 (D) B4 134

Cl R 1.34 (D) B4 135

Cl R 1.26 (D) B1 136

Cl R 1.35 (D) B4 137

Cl R 1.34 (D) B4 138

Cl R 1.37 (D) B4 139

Cl R 1.32 (D) B3 140

Cl R 1.26 (D) B1 141

Cl R 1.28 (D) B4 142

Cl R 1.29 (D) B2 143

Cl R 1.36 (D) B4 144

Cl R 1.32 (D) B4 145

Cl R 1.32 (D) B4 146

Cl R 1.31 (D) B4 147

Cl R 1.24 (D) B3 148

Cl R 1.29 (D) B4 149

Cl R 1.38 (D) B4 150

Cl R 1.26 (D) B1 151

Cl R 1.25 (D) B4 152

Cl R 1.30 (D) B4 153

Cl R 1.29 (D) B4 154

Cl R 1.34 (D) B4 155

Cl R 1.53 (B) B5 156

Cl R 1.25 (D) B4 157

Cl R 1.35 (D) B4 158

Cl R 1.39 (D) B4 159

Cl R 1.22 (D) B4 160

Cl R 1.24 (D) B3 161

Cl R 1.29 (D) B4 162

Cl R 1.28 (D) B4 163

Cl R 1.41 (D) B4 164

Cl R 1.53 (B) B5 165

Cl R 1.59 (B) B1 166

Cl R 1.26 (D) B6 167

Cl R 1.22 (E) B2 168

Cl R 1.26 (E) B8 169

Cl R 1.24 (E) B8 170

Cl R 1.25 (E) B10 171

Cl R 1.35 (E) B10 172

Cl R 1.30 (E) B10 173

Cl R 1.22 (E) B9 174

Cl R 1.19 (E) B9 175

Cl R 1.14 (E) B2 176

Cl R 1.24 (E) B7 177

Cl R 1.20 (E) B7 178

Cl R 1.12 (E) B11 179

Cl R 1.18 (E) B11 180

Cl R 1.18 (E) B11 181

Cl R 1.34 (D) B15 182

Cl R 1.36 (D) B13 183

Cl R 1.29 (D) B14 184

Cl R 1.31 (D) B12 185

Cl R 1.17 (E) B16 186

Cl R 1.24 (D) B16 187

Cl R 1.26 (D) B16 188

Br R 1.28 (D) B18 189

Cl R 1.34 (D) B17 190

Cl R 1.50 (B) B19 191

Cl R 1.34 (D) B20

S.4.3. Synthesis of Examples According to Procedure C Examples 192-196Example 192

2-Chloro-4-(3,5-dimethyl-isoxazol-4-yl)-pyridine (25 mg) and buildingblock C1 (25 mg) were dissolved in dry dioxane (1.2 ml) under inertatmosphere and palladium(II) acetate (2 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and caesiumcarbonate (81 mg) were added subsequently. The mixture was heated to100° C. and stirred for 18 h. After cooling to room temperature thereaction mixture was diluted with DCM, washed with water and brine,dried under Na₂SO₄, filtered and the solvent was evaporated underreduced pressure. The crude was purified by flash column chromatography(10 g Isolute® silica gel cartridge; gradient elution: DCM/MeOH from97/3 to 95/5) affording the title compound (49 mg). HPLC(Rt)=9.47 min(method O)

The following examples are synthesized in analogy to the preparation ofexample 192

R_(t) [min] Building # R¹ * (method) block 193

R 3.37 (L) C1 194

R 1.45 (D) C1 195

R 1.46 (D) C1 196

R 1.23 (E) C1

S.4.4. Synthesis of Examples According to Procedure D Examples 197-208Example 197

Building block D1 (0.08 g) and 3-fluoro-4-trifluoromethoxy benzaldehyde(0.05 g) were dissolved in 25% MeOH in DCM (4 ml) and the resultingsolution stirred at room temperature for 30 min. Sodium cyanoborohydride(0.02 g) was then added in one portion and the whole allowed to reactovernight. The solvent was evaporated under reduced pressure, 10% aq.K₂CO₃ (3 ml) and DCM (5 ml) were added, the layers separated, theorganic phase dried over Na₂SO₄ and evaporated to dryness. The resultingcrude was then purified by preparative LC-MS to afford the targetcompound as a TFA salt (0.03 g). HPLC (R_(t))=7.01 min (method P)

The following examples are synthesized in analogy to the preparation ofexample 197

R_(t) [min] Building # R¹ R² * (method) block 198

R 2.60 (G) D1 199

R 9.30 (O) D1

Synthesis of Example 200

D2 (0.05 g) was dissolved in EtOH (1 ml) and of 4-bromobenzaldehyde(0.081 g), HOAc (0.026 g) and a small amount of molecular sieve 4

was added and the suspension stirred at 25° C. overnight. Sodiumtriacetoxyborhydride (0.154 g) was added and again the mixture stirredfor 1 h, concentrated and suspended in MeOH, water and TFA. Afterfiltration the mixture was separated via reversed phase HPLC andfractions containing the product collected and lyophilised to provideexample 200 (0.049 g). HPLC: 1.21 min (method D)

The following examples 201-208 were synthesized in analogy to example200 from building block D2 or D3.

R_(t) [min] Building # R² * (method) block 201

R 1.20 (D) D2 202

R 1.14 (D) D2 203

R 1.21 (D) D2 204

R 1.23 (D) D2 205

R 1.23 (D) D2 206

R 1.18 (D) D2 207

R 1.18 (D) D2 208

R 1.29 (D) D3

S.4.5. Synthesis of Examples According to Procedure E

Example 209

Intermediate I12.2, (0.20 g), 3-cyclopropyl-1-methyl-1H-pyrazole-5-amine(0.14 g), potassium t-butoxide (0.10 ml of a 1M THF solution) anddioxane (2 ml) were transferred to a microwave vial and heated undermicrowave irradiation under the following conditions: max power 150 W, T150° C., 15 min; after the first cycle 0.05 mL of base were added andtwo more cycles of irradiation performed under the same conditions. Thereaction mixture was evaporated to dryness, and the oily residue waspurified by preparative LC-MS affording example 208 (as TFA salt) (0.09g). HPLC (R_(t))=7.12 min (method P)

S.4.6. Synthesis of Examples According to Procedure F Examples 210-212Example 210

Building block F1 (70 mg) was dissolved in ethanol (5 ml) and conc.hydrochloric acid (1.5 ml) was added. The solution was stirred at roomtemperature for 4 h. Ethanol was removed under reduced pressure and theresidue partitioned between saturated aqueous solution of NaHCO₃ andEtOAc. The layers were separated and the aqueous phase extracted withEtOAc. The combined organic extracts were washed with brine, dried underNa₂SO₄, filtered and the solvent was evaporated under reduced pressure.The crude was purified by flash column chromatography (5 g Isolute®silica gel cartridge; gradient elution: DCM/MeOH from 97/3 to 95/5)affording the title compound (55 mg). HPLC (R_(t))=8.08 min (method O)

Example 211-212 was synthesized in analogy to example 210.

R_(t) [min] Building # R¹ * (method) block 210

R 8.50 (O) F2 211

R 2.37 (M) F3

S.4.7. Synthesis of Examples According to Procedure G Examples 213-216Example 213

To a solution of example 181 (36 mg) in dioxane (3 ml) was addeddppfPdCl₂ (2.3 mg) and butylzinc bromide (0.137 ml of a 0.5 M solutionin THF) under an atmosphere of argon. The solution was stirred for 45min at room temperature before additional dppfPdCl₂ (2 mg) and butylzincbromide (0.07 ml of a 0.5 M solution in THF) was added and the solutionwas stirred for additional 20 min at rt. The reaction was quenched witha few drops of water, the resulting mixture was diluted with dioxane andfiltered. The filtrate was concentrated and the crude product purifiedby reversed phase HPLC affording the title compound (19 mg). HPLC: 1.41min (method D).

The following examples were synthesized in analogy to example 213

R_(t) [min] Building # R¹ * (method) block 214

R 1.34 (D) example 181 215

R 1.48 (D) example 194 216

R 1.42 (D) example 194

S.5.1 Chromatographic Methods (HPLC and HPLC Methods) Method A

Waters ZQ2000 MS, Alliance 2790 HPLC, Waters 2996 DAD (210-500 nm),Waters 2700

Autosampler

Mobile Phases:

A: Water with 0.10% TFA

B: Acetonitrile with 0.10% TFA

Time in min % A % B Flowrate in ml/min 0.00 95 5 1.00 0.10 95 5 1.003.60 2 98 1.00 6.50 2 98 1.00 7.00 95 5 1.00Stationary phase: Waters, Sunfire C18, 3.5 μm, 4,6×50 mm.Column temp: constant at 40° C.Method BWaters ZQ2000 MS, HP1100 HPLC+DAD (210-500 nm),Gilson 215 Autosampler.Mobile Phases:A: Water with 0.10% TFAB: Acetonitrile with 0.10% TFA

Time in min % A % B Flowrate in ml/min 0.00 95 5 1.50 2.00 0 100 1.502.50 0 100 1.5 2.60 95 5 1.50Stationary phase: Waters, Sunfire C18, 3.5 μm, 4.6×50 mm.Column temp: constant at 40° C.Method CAlliance 2690/2695 HPLC, waters 996/2996 DAD (210-400 nm)mobile phases:A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 2.50 0.20 95 5 2.501.50 2 98 2.50 1.70 2 98 2.50 1.90 95 5 2.50 2.20 95 5 2.50Stationary phase Merck Chromolith™ Flash RP-18e, 4.6 Mm×25 mm (at 25°C.).Method DAlliance 2690/2695 HPLC, waters 996/2996 DAD (210-400 nm) mobile phases:A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 2.80 0.30 95 5 2.801.60 2 98 2.80 1.90 2 98 2.80 2.00 95 5 2.50Stationary phase Merck Chromolith™ Flash RP-18e, 3 Mm×100 mm (at 25°C.).Method EWaters ZQ MS, Alliance 2690/2695 HPLC, Waters 996/2996Diode array detectorMobile Phases:A: Water with 0.10% NH3B: Acetonitrile with 0.10% NH3

Time in min % A % B Flowrate in ml/min 0.00 95 5 3.00 0.20 95 5 3.001.50 2 98 3.00 1.90 2 98 3.00 2.00 2 98 3.00Stationary phase: Waters, X-Bridge, C18, 3.5 μm, 4.6×20 mm.Column temp: constant at 25° C.Die Diode array detection is at the wavelength range of 210-500 nm.Method FInstrument: LC/MS ThermoFinnigan. HPLC Surveyor DAD, MSQ Quadrupole;column: Symmetry C8, 5 um, 3×150 mm;eluent A: 90% water+10% acetonitrile+ammonium formate 10 mM; eluentB=ACN 90%+10% H₂O+NH₄COOH 10 mM;gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5 min;flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCIMethod GInstrument: LC/MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; column:Sunfire MS-C18, 3.5 um, 4.6×50 mm;eluent A: water+0.1% TFA+10% acetonitrile; eluent B: acetonitrile;gradient: A/B (80:20), then to A/B (10:90) in 3.25 min for 0.75 min;flow rate:1.3 ml/min; UV Detection: 254 nm; Ion source: ESI.Method HInstrument: LC/MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; column:Xterra MS-C18, 3.5 um, 4.6×50 mm;eluent A: water+0.1% TFA+10% acetonitrile; eluent B: acetonitrile;gradient: A (100), then to A/B (10:90) in 3.25 min for 0.75 min; flowrate:1.3 ml/min; UV Detection: 254 nm; Ion source: ESI.Method LInstrument: LC/MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole. Column:Xterra MS-C8, 3.5 um, 4.6×50 mm;eluent A:water+ammonium formate 5 mM+10% acetonitrile;eluent B:acetonitrile; gradient: A 100, then to A/B (10:90) in 3.25 minfor 0.75 min; flow rate: 1.3 ml/min; UV Detection: 254 nm; Ion source:ESI.Method MInstrument: HPLC/MS Waters. Acquity HPLC® system, ZQ Quadrupole. Column:HSS C18, 1.8 um, 2.1×50 mm; eluentA: water+ammonium formate 5 mM+10% acetonitrile; eluentB:acetonitrile; gradient: A/B (90:10), then to A/B (10:90) in 1.70 minfor 0.64 min; flow rate: 0.56 ml/min; UV Detection: 254 nm; Ion source:ESI.Method NInstrument: HPLC/MS Waters. Acquity HPLC® system, ZQ Quadrupole. Column:BEH C18, 1.7 um, 2.1×50 mm; eluent A: water+0.1% TFA+10% acetonitrile;eluent B: acetonitrile; gradient: A/B (50:50), then to A/B (10:90) in1.99 min for 0.77 min; flow rate: 0.48 ml/min; UV Detection: 254 nm; Ionsource: ESI.Method O

-   Instrument: LC/MS ThermoFinnigan. HPLC Surveyor DAD, MSQ Quadrupole;    1c) column: SynergyHydro-RP80A, 4 um, 4.60×100 mm; eluent A: 90%    water+10% acetonitrile+ammonium formate 10 mM; eluent B=ACN 90%+10%    H₂O+NH₄COOH 10 mM; gradient: A (100) for 1 5 min, then to B (100) in    10 min for 1.5 min; flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion    source: APCI    Method P    Instrument: LC/MS ThermoFinnigan. HPLC Surveyor DAD, Finnigan LCQduo    Ion trap; column: Symmetry—C18, 5 um, 3×150 mm; eluent A: 95%    water+5% acetonitrile+formic acid 0.1%; eluent B=Acetonitrile 95%+5%    water+formic acid 0.1%; gradient: A/B (95/5) for 1 5 min, then to    A/B (5/95) in 10 min for 1.5 min; flow rate: 1 mL/min; UV Detection:    254 nm; Ion source: ESI    Method Q    Instrument: LC/MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole.    Column: Zorbax Eclipse Plus C18, 3.5 um, 4.6×50 mm; eluent    A:water+ammonium formate 5 mM+10% acetonitrile; eluent    B:acetonitrile; gradient: A 100, then to A/B (10:90) in 3.5 min for    1 min; flow rate: 1.3 ml/min; UV Detection: 254 nm; Ion source: ESI.

S.5.2 Chromatographic Methods: GC Methods Method 3A

Instrument: GC/MS Finnigan TRACE GC, TRACE MS Quadrupole; column:Agilent DB-5MS, 25 m×0.25 mm×0.25 um; carriage gas: Helium; flow rate: 1ml/min constant flow; oven program: 50° C. (hold 1 min), to 100° C. in10° C./min , to 200° C. in 20° C./min., to 300° C. in 30° C./min.;Detection: TRACE MS quadrupole; Ion source: EI.Microwave HeatingMicrowave apparatus type: Discover® CEM instruments, equipped with 10and 35 mL vessels;

Pharmacological Part

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.

Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The CCR3 receptor binding test is based on a K562 cell line (leukemiamyelogenic blast cells) transfected with the human chemokine receptorCCR3 (hCCR3-C1 cells). The cell membranes were prepared by disruptingthe hCCR3-C1 cells by nitrogen decomposition. The preparation wascentrifuged at 400 g 4° C. for 30 min. The supernatant was transferredinto fresh tubes followed by a second centrifugation at 48000 g, 4° C.for 1 h. The membranes were re-suspended in the SPA incubation buffer(25 mM HEPES, 25 mM MgCl₂ 6×H₂O, 1 mM CaCl₂ 2×H₂O) without bovine serumalbumin and homogenized by passing through a single use needle (Terumo,23G×1″). The membranes were stored in aliquots at −80° C.The CCR3 receptor binding assay was performed in a ScintillationProximity Assay (SPA) design with the radioligand recombinant human¹²⁵Iodine-eotaxin-1. Cell membranes of hCCR3 C1 cells were againhomogenized by passing through a single use needle (Terumo, 23G×1″) anddiluted in SPA incubation buffer in suitable concentrations (0.5-10 μgprotein/well) in 96 well microtiter plates (1450-514, Perkin Elmer). TheSPA assay was set up in the SPA incubation buffer with a final volume of200 μl and final concentration of 25 mM HEPES, 25 mM MgCl₂ 6×H₂O, 1 mMCaCl₂ 2×H₂O and 0.1% bovine serum albumin. The SPA assay mixturecontained 60 μl of the membrane suspension, 80 μl of Wheat GermAgglutinin coated PVT beads (organic scintillator, GE Healthcare,RPNQ-0001) 0.2 mg/well), 40 μl of recombinant human ¹²⁵Jodine-eotaxin-1(Biotrend), diluted in SPA buffer to a final concentration of 30.000 dpmper well, and 20 μl of the test compound (dissolved in DMSO dilutions).The SPA assay mixture was incubated for 2 h at room temperature. Boundradioactivity was determined with a scintillation counter (Micro Beta“Trilux”, Wallac). Included were controls for total binding (nodisplacer added, Bo) and non-specific binding (NSB) by adding unlabelledrecombinant human Eotaxin-1 (Biotrend, Cat #300-21) or a referencecompound.

Determination of the affinity of a test compound was calculated bysubtraction of the non-specific binding (NSB) from the total binding(Bo) or the binding in the presence of the test compound (B) at a givencompound concentration. The NSB value was set to 100% inhibition. TheBo-NSB value was set to 0% inhibition.

% inhibition values were obtained at a defined compound concentration,e.g. at 1 μM, % inhibition of the test compound was calculated by theformula 100−((B−NSB)*100/(Bo−NSB)). % inhibition values above 100% arefounded by assay variance.

The dissociation constant K_(i) was calculated by iterative fitting ofexperimental data obtained at several compound concentrations over adose range from 0.1 to 10000 nM using the law of mass action basedprogram “easy sys” (Schittkowski, Num Math 68, 129-142 (1994)).

The utility of the compounds in accordance with the present invention asinhibitors of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR3 ligandbinding, as disclosed by Ponath et al., J. Exp. Med., 183, 2437-2448(1996) and Uguccioni et al., J. Clin. Invest., 100, 11371143 (1997).Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-5 present, or a cellengineered to express a recombinant chemokine receptor, such as L1.2,K562, CHO or HEK-293 cells. Finally, blood or tissue cells, for examplehuman peripheral blood eosinophils, isolated using methods as describedby Hansel et al., J. Immunol. Methods, 145, 105-110 (1991), can beutilized in such assays. In particular, the compounds of the presentinvention have activity in binding to the CCR3 receptor in theaforementioned assays and inhibit the activation of CCR3 by CCR3ligands, including eotaxin-1, eotaxin-2, eotaxin-3, MCP-2, MCP-3, MCP-4or RANTES.

As used herein, “activity” is intended to mean a compound demonstratingan inhibition of 50% at 1 μM or higher in inhibition when measured inthe aforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as inhibitor of CCR3 receptor activity.

% inhibition and Ki values are (human Eotaxin-1 at human CCR3-Rezeptor):

CCR3 CCR3 # % inh @ 1 μM Ki (nM) 1 101 4 2 98 4 3 75 240 4 99 5 5 98 6 6100 7 7 97 7 8 99 9 9 95 12 10 98 16 11 92 27 12 84 88 13 71 373 14 60540 15 38 1111 16 98 20 17 100 5 18 96 7 19 98 7 20 97 9 21 96 11 22 8413 23 95 18 24 99 22 25 91 21 26 97 27 27 96 28 28 97 29 29 94 31 30 9547 31 93 50 32 82 145 33 83 150 34 80 152 35 83 152 36 80 159 37 80 17538 78 211 39 80 227 40 75 229 41 66 395 42 63 482 43 59 523 44 63 552 4550 713 46 44 873 47 31 1188 48 40 965 49 41 1184 50 41 1287 51 30 161552 28 1752 53 33 2010 54 90 89 55 78 235 56 76 254 57 74 302 58 76 22159 66 402 60 65 430 61 57 492 62 63 507 63 60 518 64 60 545 65 57 602 6681 658 67 52 700 68 48 715 69 55 749 70 46 791 71 49 810 72 48 875 73 48922 74 46 927 75 97 30 76 97 37 77 96 38 78 94 50 79 91 52 80 95 55 8189 111 82 87 153 83 81 223 84 77 232 85 68 350 86 65 419 91 98 18 93 9529 94 94 52 95 94 40 96 51 670 97 50 669 98 75 202 99 91 67 100 100 7101 95 45 102 100 19 103 54 1402 104 24 2399 105 99 5 106 100 3 107 9913 108 98 4 114 99 4 115 80 18 116 93 47 117 98 17 118 94 40 119 87 81120 95 35 121 98 21 122 95 30 123 95 34 124 93 41 125 97 58 126 89 71127 90 81 128 87 96 129 70 334 130 91 77 131 89 85 132 102 1 133 100 3134 101 3 135 101 3 136 100 4 137 101 4 138 101 4 139 101 5 140 98 6 14194 6 142 100 17 143 99 7 144 100 7 145 99 8 146 100 8 147 99 8 148 99 10149 99 10 150 97 10 151 95 18 152 100 12 153 99 12 154 98 14 155 98 15156 98 15 157 99 15 158 100 16 159 96 19 160 97 19 161 97 20 162 97 20163 99 23 164 96 24 165 90 62 166 60 905 167 98 6 168 99 4 169 99 19 170100 6 171 99 5 172 95 7 173 99 13 174 99 13 175 99 6 176 100 11 177 9724 178 86 108 179 95 34 180 97 16 182 99 4 183 75 232 184 100 8 185 98 1186 99 1 187 99 4 188 99 6 189 100 4 190 100 6 191 100 5 192 96 6 193 9919 196 89 95 197 44 1251 198 91 67 199 66 453 200 86 114 201 86 119 20269 390 203 75 237 204 80 299 205 76 247 206 77 357 207 75 442 208 94 43209 95 33 210 96 13 211 93 48 212 97 26 213 66 414 214 101 2

Indications

The compounds of the instant application are useful for manufacturing amedicament for the prevention and/or treatment of diseases wherein theactivity of a CCR3-receptor is involved.

Preferred is the manufacturing of a medicament for the prevention and/ortreatment of a wide variety of inflammatory, infectious, andimmunoregulatory disorders and diseases of the respiratory orgastrointestinal complaints, inflammatory diseases of the joints andallergic diseases of the nasopharynx, eyes, and skin, including asthmaand allergic diseases, eosinophilic diseases, infection by pathogenicmicrobes (which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis, aswell as diseases associated with abnormal enhanced neovascularizationsuch as age-related macular degeneration (AMD), diabetic retinopathy anddiabetic macular edema Age-related macular degeneration is a leadingcause of blindness world wide. Most blindness in AMD results frominvasion of the retina by choroidal neovascularization. CCR3 isspecifically expressed in choroidal neovascular endothelial cells of AMDpatients. In an often used mouse animal model for AMD laserinjury-induced choroidal neovascularization was dimished by geneticdepletion of CCR3 or CCR3 ligands as well as by treatment of the micewith an anti-CCR3 antibody or an CCR3 antagonist (Takeda et al, Nature2009, 460(7252):225-30)

Most preferred is the manufacturing of a medicament for the preventionand/or treatment of e.g. inflammatory or allergic diseases andconditions, including respiratory allergic diseases such as asthma,perennial and seasonal allergic rhinitis, allergic conjunctivitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);non-allergic asthma; Exercise induced bronchoconstriction; systemicanaphylaxis or hypersensitivity responses, drug allergies (e.g., topenicillin, cephalosporins), eosinophilia-myalgia syndrome due to theingestion of contaminated tryptophan, insect sting allergies; autoimmunediseases, such as rheumatoid arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, myasthenia gravis, immunethrombocytopenia (adult ITP, neonatal thrombocytopenia, paediatric ITP),immune haemolytic anaemia (auto-immune and drug induced), Evans syndrome(platelet and red cell immune cytopaenias), Rh disease of the newborn,Goodpasture's syndrome (anti-GBM disease), Celiac, Auto-immunecardio-myopathy juvenile onset diabetes; glomerulonephritis, autoimmunethyroiditis, Behcet's disease; graft rejection (e.g., intransplantation), including allograft rejection or graftversus-hostdisease; inflammatory bowel diseases, such as Crohn's disease andulcerative colitis; spondyloarthropathies; scleroderma; psoriasis(including Tcell mediated psoriasis) and inflammatory dermatoses such asan dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria; vasculitis (e.g., necrotizing, cutaneous, andhypersensitivity vasculitis); erythema nodosum; eosinophilic myositis,eosinophilic fasciitis; cancers with leukocyte infiltration of the skinor organs; chronic obstructive pulmonary disease, age-related maculardegeneration (AMD), diabetic retinopathy and diabetic macular edema.

Method of Treatment

Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, chronic obstructive pulmonarydisease, infection by pathogenic microbes (which, by definition,includes viruses), autoimmune pathologies such as the rheumatoidarthritis and atherosclerosis as well as age-related maculardegeneration (AMD), diabetic retinopathy and diabetic macular edema.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation,infectious diseases or abnormal enhanced neovascularization. As aresult, one or more inflammatory process, such as leukocyte emigration,adhesion, chemotaxis, exocytosis (e.g., of enzymes, growth factors,histamine) or inflammatory mediator release, survival or proliferationof CCR3 expressing cells is inhibited. For example, eosinophilicinfiltration to inflammatory sites (e.g., in asthma or allergicrhinitis) can be inhibited according to the present method. Inparticular, the compound of the following examples has activity inblocking the activation and migration of cells expressing the CCR3receptor using the appropriate chemokines in the aforementioned assays.In another instance, endothelial proliferation and neovascularizationmay be inhibited (i.e., reduced or prevented). As a result abnormalenhanced neovascularization, i.e. of the retina, is inhibited.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom inhibition of chemokine receptor activity is desired.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); chronicobstructive pulmonary disease (including rhinovirus-inducedexacerbations); systemic anaphylaxis or hypersensitivity responses, drugallergies (e.g., to penicillin, cephalosporins), eosinophilia-myalgiasyndrome due to the ingestion of contaminated tryptophan, insect stingallergies; autoimmune diseases, such as rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, systemic lupus erythematosus, myastheniagravis, juvenile onset diabetes; glomerulonephritis, autoimmunethyroiditis, Behcet's disease; graft rejection (e.g., intransplantation), including allograft rejection or graftversus-hostdisease; inflammatory bowel diseases, such as Crohn's disease andulcerative colitis; spondyloarthropathies; scleroderma; psoriasis(including Tcell mediated psoriasis) and inflammatory dermatoses such asan dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria; vasculitis (e.g., necrotizing, cutaneous, andhypersensitivity vasculitis); eosinophilic myositis, eosinophilicfasciitis; cancers with leukocyte infiltration of the skin or organs.Other diseases or conditions in which undesirable inflammatory responsesare to be inhibited can be treated, including, but not limited to,reperfusion injury, atherosclerosis, certain hematologic malignancies,cytokine-induced toxicity (e.g., septic shock, endotoxic shock),polymyositis, dermatomyositis. Infectious diseases or conditions ofhuman or other species which can be treated with inhibitors of chemokinereceptor function, include, but are not limited to, HIV.

Also diseases associated with abnormal enhanced neovascularization suchas age-related macular degeneration (AMD), diabetic retinopathy anddiabetic macular edema can be treated.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.

Specifically, such compounds may be provided in a commerical kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Combinations

The compounds of general formula 1 may be used on their own or combinedwith other active substances of formula 1 according to the invention.The compounds of general formula 1 may optionally also be combined withother pharmacologically active substances. These include,β2-adrenoceptor-agonists (short and long-acting), anti-cholinergics(short and long-acting), anti-inflammatory steroids (oral and topicalcorticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor(BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, HistamineH4 receptor antagonists, dual Histamine H1/H3-receptor antagonists,PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases asfor example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-κB signalling pathway as for example IKK2 kinaseinhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosyntheseinhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors,Non-steroidale anti-inflammatory agents (NSAIDs), CRTH2 antagonists,DP1-receptor modulators, Thromboxane receptor antagonists, CCR3antagonists, CCR⁴ antagonists, CCR¹ antagonists, CCR5 antagonists, CCR6antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR³⁰antagonists, CXCR³ antagonists, CXCR⁴ antagonists, CXCR² antagonists,CXCR¹ antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR³antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphatereceptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosinereceptor modulators as for example A2a-agonists, modulators ofpurinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase(HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors,PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-betaconverting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators,HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIPagonists, GABAa receptor antagonist, ENaC-inhibitors, Melanocortinreceptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists,Endothelin antagonists, TNFα antagonists, anti-TNF antibodies,anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies,anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies,anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies,anti-OX40 antibodies, mucoregulators, immunotherapeutic agents,compounds agianst swelling of the airways, compounds against cough, VEGFinhibitors, but also combinations of two or three active substances.

Preferred are betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, butalso combinations of two or three active substances, i.e.:

-   -   Betamimetics with corticosteroids, PDE4-inhibitors,        CRTH2-inhibitors or LTD4-antagonists,    -   Anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists,    -   Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or        LTD4-antagonists    -   PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists    -   CRTH2-inhibitors with LTD4-antagonists.

Pharmaceutical Forms

Suitable preparations for administering the compounds of formula 1include for example tablets, capsules, suppositories, solutions andpowders etc. The content of the pharmaceutically active compound(s)should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-%of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral use the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonateand dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatine and the like. Lubricantssuch as magnesium stearate, sodium laurylsulphate and talc may also beused to produce the tablets. In the case of aqueous suspensions theactive substances may be combined with various flavour enhancers orcolourings in addition to the above-mentioned excipients.

For administering the compounds of formula 1 it is particularlypreferred according to the invention to use preparations orpharmaceutical formulations which are suitable for inhalation. Inhalablepreparations include inhalable powders, propellant-containingmetered-dose aerosols or propellant-free inhalable solutions. Within thescope of the present invention, the term propellant-free inhalablesolutions also include concentrates or sterile inhalable solutions readyfor use. The formulations which may be used within the scope of thepresent invention are described in more detail in the next part of thespecification.

The inhalable powders which may be used according to the invention maycontain 1 either on its own or in admixture with suitablephysiologically acceptable excipients.

If the active substances 1 are present in admixture with 40physiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare these inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients. Preferably, mono- or disaccharides are used, while theuse of lactose or glucose is preferred, particularly, but notexclusively, in the form of their hydrates. For the purposes of theinvention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.It may sometimes seem appropriate to add finer excipient fractions withan average particle size of 1 to 9 μm to the excipient mentioned above.These finer excipients are also selected from the group of possibleexcipients listed hereinbefore. Finally, in order to prepare theinhalable powders according to the invention, micronised activesubstance 1, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and finally mixing the ingredients togetherare known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain the compounds 1 dissolved in the propellant gas orin dispersed form. The compounds 1 may be contained in separateformulations or in a common formulation, in which the compounds 1 areeither both dissolved, both dispersed or in each case only one componentis dissolved and the other is dispersed. The propellant gases which maybe used to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The abovementioned propellant gases may beused on their own or mixed together. Particularly preferred propellantgases are halogenated alkane derivatives selected from TG134a and TG227and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-solvents, stabilisers, surfactants, antioxidants,lubricants and pH adjusters. All these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art(MDIs=metered dose inhalers).

Moreover, the active substances 1 according to the invention may beadministered in the form of propellant-free inhalable solutions andsuspensions. The solvent used may be an aqueous or alcoholic, preferablyan ethanolic solution. The solvent may be water on its own or a mixtureof water and ethanol. The relative proportion of ethanol compared withwater is not limited but the maximum is preferably up to 70 percent byvolume, more particularly up to 60 percent by volume and most preferablyup to 30 percent by volume. The remainder of the volume is made up ofwater. The solutions or suspensions containing 1 are adjusted to a pH of2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjustedusing acids selected from inorganic or organic acids. Examples ofparticularly suitable inorganic acids include hydrochloric acid,hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.Examples of particularly suitable organic acids include ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulphuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g. as flavourings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

If desired, the addition of editic acid (EDTA) or one of the known saltsthereof, sodium edetate, as stabiliser or complexing agent may beomitted in these formulations. Other embodiments may contain thiscompound or these compounds. In a preferred embodiment the content basedon sodium edetate is less than 100 mg/100 ml, preferably less than 50mg/100 ml, more preferably less than 20 mg/100 ml. Generally, inhalablesolutions in which the content of sodium edetate is from 0 to 10 mg/100ml are preferred. Co-solvents and/or other excipients may be added tothe propellant-free inhalable solutions. Preferred co-solvents are thosewhich contain hydroxyl groups or other polar groups, e.g.alcohols-particularly isopropyl alcohol, glycols-particularlypropyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether,glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acidesters. The terms excipients and additives in this context denote anypharmacologically acceptable substance which is not an active substancebut which can be formulated with the active substance or substances inthe physiologically suitable solvent in order to improve the qualitativeproperties of the active substance formulation. Preferably, thesesubstances have no pharmacological effect or, in connection with thedesired therapy, no appreciable or at least no undesirablepharmacological effect. The excipients and additives include, forexample, surfactants such as soya lecithin, oleic acid, sorbitan esters,such as polysorbates, polyvinylpyrrolidone, other stabilisers,complexing agents, antioxidants and/or preservatives which guarantee orprolong the shelf life of the finished pharmaceutical formulation,flavourings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, forexample, provided that it has not already been used to adjust the pH,vitamin A, vitamin E, tocopherols and similar vitamins and provitaminsoccurring in the human body.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly cetyl pyridinium chloride, benzalkonium chloride orbenzoic acid or benzoates such as sodium benzoate in the concentrationknown from the prior art. The preservatives mentioned above arepreferably present in concentrations of up to 50 mg/100 ml, morepreferably between 5 and 20 mg/100 ml.

Preferred formulations contain, in addition to the solvent water and theactive substance 1, only benzalkonium chloride and sodium edetate. Inanother preferred embodiment, no sodium edetate is present.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds offormula 1 are characterised by a high potency even at doses in the μgrange. The compounds of formula 1 may also be used effectively above theμg range. The dosage may then be in the gram range, for example.

In another aspect the present invention relates to the above-mentionedpharmaceutical formulations as such which are characterised in that theycontain a compound of formula 1, particularly the above-mentionedpharmaceutical formulations which can be administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 1 100 mg lactose 140 mg maizestarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

The finely ground active substance, lactose and some of the maize starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet granulated anddried. The granules, the remaining maize starch and the magnesiumstearate are screened and mixed together. The mixture is pressed intotablets of suitable shape and size.

B) Tablets per tablet active substance 1 80 mg lactose 55 mg maizestarch 190 mg  microcrystalline cellulose 35 mg polyvinylpyrrolidone 15mg sodium carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance 1 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make the solutionisotonic. The resulting solution is filtered to remove pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilised and heat-sealed. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

D) Metering aerosol active substance 1 0.005 sorbitan trioleate 0.1monofluorotrichloromethane and ad 100 TG134a:TG227 2:1

The suspension is transferred into a conventional aerosol container withmetering valve. Preferably 50 μl suspension are released on eachactuation. The active substance may also be released in higher doses ifdesired (e.g. 0.02 wt.-%).

E) Solutions (in mg/100 ml) active substance 1 333.3 mg  benzalkoniumchloride 10.0 mg EDTA 50.0 mg HCl (1N) ad pH 2.4

This solution can be prepared in the usual way.

F) Inhalable powder active substance 1 12 μg lactose monohydrate ad 25mg

The inhalable powder is prepared in the usual way by mixing theindividual ingredients.

What is claimed is:
 1. A compound of formula 1,

wherein A is CH₂, O or N—C₁₋₆-alkyl; R¹ is selected from NHR^(1.1),NMeR^(1.1); NHR^(1.2), NMeR^(1.2); NHCH₂—R^(1.3); NH—C₃₋₆-cycloalkyl,whereas optionally one carbon atom is replaced by a nitrogen atom,whereas the ring is optionally substituted with one or two residuesselected from the group consisting of C₁₋₆-alkyl, O—C₁₋₆-alkyl,NHSO₂-phenyl, NHCONH-phenyl, halogen, CN, SO₂—C₁₋₆-alkyl,COO—C₁₋₆-alkyl; a C_(9 or 10)-bicyclic-ring, whereas one or two carbonatoms are replaced by nitrogen atoms and the ring system is bound via anitrogen atom to the basic structure of formula 1 and whereas the ringsystem is optionally substituted with one or two residues selected fromthe group consisting of C₁₋₆-alkyl, COO—C₁₋₆-alkyl, C₁₋₆-haloalkyl,O—C₁₋₆-alkyl, NO₂, halogen, CN, NHSO₂—C₁₋₆-alkyl, methoxyphenyl; a groupselected from NHCH(pyridinyl)CH₂COO—C₁₋₆-alkyl,NHCH(CH₂O—C₁₋₆-alkyl)-benzoimidazolyl, optionally substituted withhalogen or CN; or 1-aminocyclopentyl, optionally substituted withmethyl-oxadiazole; R^(1.1) is phenyl, optionally substituted with one ortwo residues selected from the group consisting of C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,C₂₋₆-alkenylene-OH, C₂₋₆-alkynylene-OH, CH₂CON(C₁₋₆-alkyl)₂,CH₂NHCONH—C₃₋₆-cycloalkyl, CN, CO-pyridinyl, CONR^(1.1.1)R^(1.1.2),COO—C₁₋₆-alkyl, N(SO₂—C₁₋₆-alkyl)(CH₂CON(C₁₋₄-alkyl)₂) O—C₁₋₆-alkyl,O-pyridinyl, SO₂—C₁₋₆-alkyl, SO₂—C₁₋₆-alkylen-OH, SO₂—C₃₋₆-cycloalkyl,SO₂-piperidinyl, SO₂NH—C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂, halogen, CN,CO-morpholinyl, CH₂-pyridinyl or a heterocyclic ring optionallysubstituted with one or two residues selected from the group consistingof C₁₋₆-alkyl, NHC₁₋₆-alkyl and ═O; R^(1.1.1) H, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl, CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl,CH₂-furanyl, C₁₋₆-alkylen-OH or thiadiazolyl, optionally substitutedwith C₁₋₆-alkyl; R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl; or R^(1.1.1)and R^(1.1.2) together are forming a four-, five- or six-memberedcarbocyclic ring, optionally containing one N or O, replacing a carbonatom of the ring, optionally substituted with one or two residuesselected from the group consisting of C₁₋₆-alkyl, C₁₋₄-alkylene-OH, OH,═O; or R^(1.1) is phenyl, wherein two adjacent residues are togetherforming a five- or six-membered carbocyclic aromatic or non-aromaticring, optionally containing independently from each other one or two N,S, or SO₂, replacing a carbon atom of the ring, wherein the ring isoptionally substituted with C₁₋₄-alkyl or ═O; R^(1.2) is selected fromheteroaryl, optionally substituted with one or two residues selectedfrom the group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₆-cycloalkyl, CH₂COO—C₁₋₆-alkyl, CONR^(1.2.1)R^(1.2.2), COR^(1.2.3),COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN, SO₂N(C₁₋₆-alkyl)₂ orheteroaryl optionally substituted with one or two residues selected fromthe group consisting of C₁₋₆-alkyl; heteroaryl, optionally substitutedwith a five- or six-membered carbocyclic non-aromatic ring containingindependently from each other two N, O, S, or SO₂, replacing a carbonatom of the ring; an aromatic or non-aromatic C_(9 or 10)-bicyclic-ring,whereas one or two carbon atoms are replaced by N, O or S eachoptionally substituted with one or two residues selected from the groupconsisting of N(C₁₋₆-alkyl)₂, CONH—C₁₋₆-alkyl, ═O; a heterocyclicnon-aromatic ring, optionally substituted with pyridinyl;4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted withNHCO—C₁₋₆-alkyl, R1.2.1 H, C₁₋₆-alkyl, C₁₋₆-alkylene-C₃₋₆-cycloalkyl,C₁₋₄-alkylene-phenyl, C₁₋₄-alkylene-furanyl, C₃₋₆-cycloalkyl,C₁₋₄-alkylene-O—C₁₋₄-alkyl, C₁₋₆-haloalkyl or a five- or six-memberedcarbocyclic non-aromatic ring, optionally containing independently fromeach other one or two N, O, S, or SO₂, replacing a carbon atom of thering, optionally substituted with 4-cyclopropylmethyl-piperazinylR^(1.2.2) H, C₁₋₆-alkyl; R^(1.2.3) a five- or six-membered carbocyclicnon-aromatic ring, optionally containing independently from each otherone or two N, O, S, or SO₂, replacing a carbon atom of the ring; R^(1.3)is selected from phenyl, heteroaryl or indolyl, each optionallysubstituted with one or two residues selected from the group consistingof C₁₋₆-alkyl, C₃₋₆-cycloalkyl, O—C₁₋₆-alkyl, O—C₁₋₆-haloalkyl, phenyl,heteroaryl; R² is selected from the group consisting ofC₁₋₆-alkylene-phenyl, C₁₋₆-alkylene-naphthyl, andC₁₋₆-alkylene-heteroaryl; each optionally substituted with one, two orthree residues selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-haloalkyl, O—C₁₋₆-alkyl, O—C₁₋₆-haloalkyl, halogen; R³ is H,C₁₋₆-alkyl; R⁴ is H, C₁₋₆-alkyl; or R³ and R⁴ together are forming aCH₂—CH₂ group.
 2. The compound of formula 1 according to claim 1,wherein A is CH₂, O or N—C₁₋₄-alkyl; R¹ is selected from NHR^(1.1),NMeR^(1.1); NHR^(1.2), NMeR^(1.2); NHCH₂—R^(1.3); NH—C₃₋₆-cycloalkyl,whereas optionally one carbon atom is replaced by a nitrogen atom,whereas the ring is optionally substituted with one or two residuesselected from the group consisting of C₁₋₆-alkyl, O—C₁₋₆-alkyl,NHSO₂-phenyl, NHCONH-phenyl, halogen, CN, SO₂—C₁₋₆-alkyl,COO—C₁₋₆-alkyl; a C_(9 or 10)-bicyclic-ring, whereas one or two carbonatoms are replaced by nitrogen atoms and the ring system is bound via anitrogen atom to the basic structure of formula 1 and whereas the ringsystem is optionally substituted with one or two residues selected fromthe group consisting of C₁₋₆-alkyl, COO—C₁₋₆-alkyl, C₁₋₆-haloalkyl,O—C₁₋₆-alkyl, NO₂, halogen, CN, NHSO₂—C₁₋₆-alkyl, m-methoxyphenyl; agroup selected from NHCH(pyridinyl)CH₂COO—C₁₋₆-alkyl,NHCH(CH₂O—C₁₋₆-alkyl)-benzoimidazolyl, optionally substituted with Cl;or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;R1.1 is phenyl, optionally substituted with one or two residues selectedfrom the group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl,CH₂CON(C₁₋₆-alkyl)₂, CH₂NHCONH—C₃₋₆-cycloalkyl, CN,CONR^(1.1.1)R^(1.1.2), COO—C₁₋₆-alkyl, O—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl,SO₂—C₁₋₆-alkylen-OH, SO₂—C₃₋₆-cycloalkyl, SO₂-piperidinyl,SO₂NH—C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂, halogen, CN, CO-morpholinyl,CH₂-pyridinyl or a heterocyclic ring optionally substituted with one ortwo residues selected from the group consisting of C₁₋₆-alkyl,NHC₁₋₆-alkyl, ═O; R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,C₁₋₆-haloalkyl, CH₂CON(C₁₋₆-alkyl)₂, CH₂CO-azetindinyl,C₁₋₆-alkylen-C₃₋₆-cycloalkyl, CH₂-pyranyl, CH₂-tetrahydrofuranyl,CH₂-furanyl, C₁₋₆-alkylen-OH or thiadiazolyl, optionally substitutedwith C₁₋₆-alkyl; R^(1.1.2) H, C₁₋₆-alkyl, SO₂C₁₋₆-alkyl; or R^(1.1.1)and R^(1.1.2) together are forming a four-, five- or six-memberedcarbocyclic ring, optionally containing one O, replacing a carbon atomof the ring, optionally substituted with one or two residues selectedfrom the group consisting of CH₂OH R^(1.2) is selected from heteroaryl,optionally substituted with one or two residues selected from the groupconsisting of C₁₋₆-alkyl, C₃₋₆-cycloalkyl, CH₂COO—C₁₋₆-alkyl,CONR^(1.2.1)R^(1.2.2), COO—C₁₋₆-alkyl, CONH₂, O—C₁₋₆-alkyl, halogen, CN,CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally substitutedwith one or two residues selected from the group consisting ofC₁₋₆-alkyl; benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,tetrahydro-quinolinyl, each optionally substituted with one or tworesidues selected from the group consisting of N(C₁₋₆-alkyl)₂,CONH—C₁₋₆alkyl, ═O; piperidinyl, optionally substituted with pyridinyl;4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted withNHCO—C₁₋₆alkyl, R^(1.2.1) H, C₁₋₆-alkyl; R^(1.2.2) H, C₁₋₆-alkyl;R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl,indolyl or oxadiazolyl, each optionally substituted with one or tworesidues selected from the group consisting of C₁₋₆-alkyl,C₃₋₆-cycloalkyl, O—C₁₋₆-alkyl, O—C₁₋₆-haloalkyl; R² is selected fromCH₂-phenyl or CH₂-naphthyl, both optionally substituted with one or tworesidues selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-haloalkyl, O—C₁₋₆-alkyl, O—C₁₋₆-haloalkyl, halogen; orCH₂-thiophenyl, optionally substituted with one or two residues selectedfrom the group consisting of halogen; R³ is H, C₁₋₄-alkyl; R⁴ is H,C₁₋₄-alkyl; or R³ and R⁴ together are forming a CH₂—CH₂ group.
 3. Thecompound of formula 1 according to claim 1, wherein A is CH₂, O or NMe;R¹ is selected from NHR^(1.1), NMeR^(1.1); NHR^(1.2), NMeR^(1.2);NHCH₂—R^(1.3); NH-cyclohexyl, optionally substituted with one or tworesidues selected from the group consisting of C₁₋₄-alkyl, NHSO₂-phenyl,NHCONH-phenyl, halogen; NH-pyrrolidinyl, optionally substituted with oneor two residues selected from the group consisting of SO₂—C₁₋₄-alkyl,COO—C₁₋₄-alkyl; piperidinyl, optionally substituted with one or tworesidues selected from the group consisting of NHSO₂—C₁₋₄-alkyl,m-methoxyphenyl; dihydro-indolyl, dihydro-isoindolyl,tetrahydro-quinolinyl or tetrahydro-isoquinolinyl, optionallysubstituted with one or two residues selected from the group consistingof C₁₋₄-alkyl, COO—C₁₋₄-alkyl, C₁₋₄-haloalkyl, O—C₁₋₄-alkyl, NO₂,halogen; a group selected from NHCH(pyridinyl)CH₂COO—C₁₋₄-alkyl,NHCH(CH₂O—C₁₋₄-alkyl)-benzoimidazolyl, optionally substituted with Cl;or 1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;R^(1.1) is phenyl, optionally substituted with one or two residuesselected from the group consisting of C₁₋₄-alkyl, C₁₋₄-haloalkyl,CH₂CON(C₁₋₄-alkyl)₂, CH₂NHCONH—C₃₋₆-cycloalkyl, CN,CONR^(1.1.1)R^(1.1.2), COO—C₁₋₄-alkyl, O—C₁₋₄-alkyl, SO₂—C₁₋₄-alkyl,SO₂—C₁₋₄-alkylen-OH, SO₂—C₃₋₆-cycloalkyl, SO₂-piperidinyl,SO₂NH—C₁₋₄-alkyl, SO₂N(C₁₋₄-alkyl)₂, halogen, CO-morpholinyl,CH₂-pyridinyl, or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl,pyrimidinyl, each optionally substituted with one or two residuesselected from the group consisting of C₁₋₄-alkyl, NHC₁₋₄-alkyl, ═O;R^(1.1.1) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₄-haloalkyl,CH₂CON(C₁₋₄-alkyl)₂, CH₂CO-azetindinyl, C₁₋₄alkylen-C₃₋₆-cycloalkyl,CH₂-pyranyl, CH₂-tetrahydrofuranyl, CH₂-furanyl, C₁₋₄-alkylen-OH orthiadiazolyl, optionally substituted with C₁₋₄-alkyl; R^(1.1.2) H,C₁₋₄-alkyl, SO₂C₁₋₄-alkyl; or R^(1.1.1) and R^(1.1.2) together areforming a four-, five- or six-membered carbocyclic ring, optionallycontaining one O, replacing a carbon atom of the ring, optionallysubstituted with one or two residues selected from the group consistingof CH₂OH R^(1.2) is selected from pyridinyl, pyridazinyl, pyrrolyl,pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substitutedwith one or two residues selected from the group consisting ofC₁₋₄-alkyl, C₃₋₆-cycloalkyl, CH₂COO—C₁₋₄-alkyl, CONR^(1.2.1)R^(1.2.2),COO—C₁₋₄-alkyl, CONH₂, O—C₁₋₄-alkyl, halogen, CO-pyrrolidinyl,CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,oxadiazolyl, each optionally substituted with one or two residuesselected from the group consisting of C₁₋₄-alkyl; benzothiazolyl,indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, eachoptionally substituted with one or two residues selected from the groupconsisting of N(C₁₋₄-alkyl)₂, CONH—C₁₋₄-alkyl, ═O; piperidinyl,optionally substituted with pyridinyl;4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted withNHCO—C₁₋₄-alkyl, R^(1.2.1) H, C₁₋₄-alkyl; R^(1.2.2) H, C₁₋₄-alkyl;R^(1.3) is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl,indolyl or oxadiazolyl, each optionally substituted with one or tworesidues selected from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkyl, O—C₁₋₄-alkyl, O—C₁₋₄-haloalkyl; R² is selected fromCH₂-phenyl or CH₂-naphthyl, both optionally substituted with one or tworesidues selected from the group consisting of C₁₋₄-alkyl,C₁₋₄-haloalkyl, O—C₁₋₄-haloalkyl, halogen; or CH₂-thiophenyl, optionallysubstituted with one or two residues selected from the group consistingof halogen; R³ is H; R⁴ is H; or R³ and R⁴ together are forming aCH₂—CH₂ group.
 4. The compound of formula 1 according to claim 1,wherein A is CH₂, O or NMe; R¹ is selected from NHR^(1.1), NMeR^(1.1);NHR^(1.2), NMeR^(1.2); NHCH₂—R^(1.3); NH-piperidinyl, optionallysubstituted with pyridinyl; NH-cyclohexyl, optionally substituted withone or two residues selected from the group consisting of t-Bu,NHSO₂-phenyl, NHCONH-phenyl, F; NH-pyrrolidinyl, optionally substitutedwith one or two residues selected from the group consisting of SO₂Me,COO-t-Bu; piperidinyl, optionally substituted with one or two residuesselected from the group consisting of NHSO₂-n-Bu, m-methoxyphenyl;dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolinyl ortetrahydro-isoquinolinyl, optionally substituted with one or tworesidues selected from the group consisting of Me, COOMe, CF₃, OMe, NO₂,F, Br; a group selected from NHCH(pyridinyl)CH₂COOMe,NHCH(CH₂OMe)-benzoimidazolyl, optionally substituted with Cl; or1-aminocyclopentyl, optionally substituted with methyl-oxadiazolyl;R^(1.1) is phenyl, optionally substituted with one or two residuesselected from the group consisting of Me, Et, t-Bu, CF₃, CH₂CONMe₂,CH₂NHCONH-cyclohexyl, CN, CONR^(1.1.1)R^(1.1.2), COOMe, COOEt, OMe,SO₂Me, SO₂CH₂CH₂OH, SO₂Et, SO₂-cyclopropyl, SO₂-piperidinyl, SO₂NHEt,SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-pyridinyl, or imidazolidinyl,piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionallysubstituted with one or two residues selected from the group consistingof Me, NHMe, ═O; R^(1.1.1) H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr,CH₂-t-Bu, CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl,CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydro-furanyl,CH₂-furanyl, CH₂CH₂OH or thiadiazolyl, optionally substituted with Me;R^(1.1.2) H, Me, Et, SO₂Me, SO₂Et or R^(1.1.1) and R^(1.1.2) togetherare forming a four-, five- or six-membered carbocyclic ring, optionallycontaining one O, replacing a carbon atom of the ring, optionallysubstituted with one or two residues selected from the group consistingof CH₂OH R^(1.2) is selected from pyridinyl, pyrrolyl, pyrazolyl,isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one ortwo residues selected from the group consisting of Me, Et, Pr, Bu,cyclopropyl, CH₂COOEt, CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe,Cl, Br CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl,tetrazolyl, isoxazolyl, oxadiazolyl, each optionally substituted Me;benzothiazolyl, indazolyl, dihydro-indolyl, indanyl,tetrahydro-quinolinyl, each optionally substituted with one or tworesidues selected from the group consisting of NMe₂, CONHMe, ═O;4,5-dihydro-naphtho[2,1-d]thiazole, optionally substituted with NHCOMe,R^(1.2.1) H, Me; R^(1.2.2) H, Me; R^(1.3) is selected from phenyl,pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, eachoptionally substituted with one or two residues selected from the groupconsisting of Me, Et, Pr, cyclopentyl, OMe, OCHF₂; R² is selected fromCH₂-phenyl or CH₂-naphthyl, both optionally substituted with one or tworesidues selected from the group consisting of CH₃, CF₃, OCF₃, F, Cl,Br, Et; or CH₂-thiophenyl, optionally substituted with one or tworesidues selected from the group consisting of Cl, Br; R³ is H; R⁴ is H;or R³ and R⁴ together are forming a CH₂—CH₂ group.
 5. The compound offormula 1 according to claim 1, wherein A is CH₂, O or NMe; R¹ isselected from NHR^(1.1) NHR^(1.2), R^(1.1) is phenyl, optionallysubstituted with one or two residues selected from the group consistingof Me, Et, Bu, CF₃, CH₂CONMe₂, CH₂NHCONH-cyclohexyl, CN,CONR^(1.1.1)R^(1.1.2), COOMe, COOEt, OMe, SO₂Me, SO₂CH₂CH₂OH, SO₂Et,SO₂-cyclopropyl, SO₂-piperidinyl, SO₂NHEt, SO₂NMeEt, F, Cl,CO-morpholinyl, CH₂-pyridinyl, or imidazolidinyl, piperidinyl,oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with oneor two residues selected from the group consisting of Me, NHMe, ═O;R^(1.1.1) H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr, CH₂-t-Bu,CH(CH₃)CH₂CH₃, CH₂CHF₂, CH₂CONMe₂, CH₂CO-azetindinyl, CH₂-cyclopropyl,CH₂-cyclobutyl, CH₂-pyranyl, CH₂-tetrahydro-furanyl, CH₂-furanyl,CH₂CH₂OH or thiadiazolyl, optionally substituted with Me; R^(1.1.2) H,Me, Et, SO₂Me, SO₂Et or R^(1.1.1) and R^(1.1.2) together are forming afour-, five- or six-membered carbocyclic ring, optionally containing oneO, replacing a carbon atom of the ring, optionally substituted with oneor two residues selected from the group consisting of CH₂OH R^(1.2) isselected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl,thiadiazolyl, optionally substituted with one or two residues selectedfrom the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH₂COOEt,CONR^(1.2.1)R^(1.2.2), COOMe, COOEt, CONH₂, OMe, Cl, Br CO-pyrrolidinyl,CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,oxadiazolyl, each optionally substituted Me; benzothiazolyl, indazolyl,dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionallysubstituted with one or two residues selected from the group consistingof NMe₂, CONHMe, ═O; 4,5-dihydro-naphtho [2,1-d]thiazole, optionallysubstituted with NHCOMe, R^(1.2.1) H, Me; R^(1.2.2) H, Me; R² isselected from CH₂-phenyl or CH₂-naphthyl, both optionally substitutedwith one or two residues selected from the group consisting of CH₃, CF₃,OCF₃, F, Cl, Br, Et R³ is H; R⁴ is H.
 6. The compound of formula 1according to claim 1, wherein A is CH₂, O or NMe; R¹ is selected fromthe group consisting of

R² is selected from the group consisting of

R³ is H; R⁴ is H; or R³ and R⁴ together are forming a CH₂—CH₂ group. 7.The compound of formula 1 according to claim 1, wherein the compound ispresent in the form of the individual optical isomers, a mixture of theindividual enantiomers, a racemate or in the form of theenantiomerically pure compounds.
 8. The compound of formula 1 accordingto claim 1, wherein the compound is present in the form of theR-enantiomer R-1


9. A pharmaceutical composition of matter comprising one or morecompounds of formula 1 according to claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 10. A pharmaceutical composition ofmatter according to claim 9 further comprising a substance selected fromthe group consisting of betamimetics, anticholinergics, corticosteroids,PDE4 inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists,SYK-inhibitors and combinations of any of such substances.
 11. Thecompound of formula 1 according to claim 1, wherein the compound is


12. The compound of formula 1 according to claim 1, wherein the compoundis


13. The compound of formula 1 according to claim 1, wherein the compoundis


14. The compound of formula 1 according to claim 1, wherein the compoundis


15. The compound of formula 1 according to claim 1, wherein the compoundis


16. The compound of formula 1 according to claim 1, wherein the compoundis


17. The compound of formula 1 according to claim 1, wherein the compoundis


18. The compound of formula 1 according to claim 1, wherein the compoundis


19. The compound of formula 1 according to claim 1, wherein the compoundis


20. The compound of formula 1 according to claim 1, wherein


21. The compound of formula 1 according to claim 1, wherein the compoundis


22. The compound of formula 1 according to claim 1, wherein the compoundis


23. The compound of formula 1 according to claim 1, wherein the compoundis


24. The compound of formula 1 according to claim 1, wherein the compoundis


25. The compound of formula 1 according to claim 1, wherein the compoundis


26. The compound of formula 1 according to claim 1, wherein the compoundis


27. The compound of formula 1 according to claim 1, wherein the compoundis


28. The compound of formula 1 according to claim 1, wherein the compoundis


29. The compound of formula 1 according to claim 1, wherein the compoundis


30. The compound of formula 1 according to claim 1, wherein the compoundis


31. The compound of formula 1 according to claim 1, wherein the compoundis


32. The compound of formula 1 according to claim 1, wherein the compoundis


33. The compound of formula 1 according to claim 1, wherein the compoundis


34. The compound of formula 1 according to claim 1, wherein the compoundis


35. The compound of formula 1 according to claim 1, wherein the compoundis


36. The compound of formula 1 according to claim 1, wherein the compoundis


37. The compound of formula 1 according to claim 1, wherein the compoundis


38. The compound of formula 1 according to claim 1, wherein the compoundis


39. The compound of formula 1 according to claim 1, wherein the compoundis


40. The compound of formula 1 according to claim 1, wherein the compoundis


41. The compound of formula 1 according to claim 1, wherein the compoundis


42. The compound of formula 1 according to claim 1, wherein the compoundis


43. The compound of formula 1 according to claim 1, wherein the compoundis


44. The compound of formula 1 according to claim 1, wherein the compoundis


45. The compound of formula 1 according to claim 1, wherein the compoundis